Pain

Table of Contents
Origins of IBS Pain
IBS Pain Links With Other Pain Disorders
IBS Pain Locations
IBS Pain Timing
Psychological Therapies For IBS Pain
Medications For IBS Pain
Alternative Treatments For IBS Pain
Further Reading And References

Origins of IBS Pain

IBS pain is regarded as chronic (lasting 6 months or longer, constant or recurring frequently for extended periods) and visceral (involving internal organs). When in pain, a person might assume that there is internal damage that needs to be found and corrected, but with IBS, all tests come back normal.

This pain originates from alterations in the communication between the brain and the gut (brain-gut axis):

• Signals are sent from internal organs via the spinal chord to the brain
• The spinal chord acts as a type of ‘gate’ for these signals, which the brain can open or close
• When the gate is closed pain signals are blocked
• When the gate is open the pain signals are increased and ‘turned up’ in the brain
• Being under stress for extended periods or emotionally distressed open the gate and impacts the brain’s ability to reduce pain signals (174)
• The brains ability to modify pain signals received is known as the gate control theory of pain
• Additionally, life experiences including neglect, abuse, divorce, death of a loved one or trauma can reduce the central nervous system’s ability to control these signals

(1) (3)

• Visceral hypersensitivity and visceral pain occur when signals from normal activity of the gut are sent to the brain and are increased causing a greater perception of pain by the brain. This increase in signals can be caused by:
  • altered gut bacteria. Interestingly, in a study where mice were inoculated with the faecal microbiota of patients with disorders of the gut/brain interaction (DGBI), the visceral hypersensitivity symptom was transferred to them from the donor (186)
  • changes in the reaction to foods
  • alterations in the activation of the gut immune system

(13)

Unfortunately when chronic pain is experienced over long periods of time, the brain becomes even more sensitised to the pain. Chronic pain causes more pain (175). Injuries to the gut including for example, food poisoning, gut infections, intestinal flu, abdominal surgery may be overcome but the nerves in the gut retain a sensory memory of these, thus prolonging pain (127).

In a study, colon biopsy samples were taken from IBS-D patients. The scientists found a significant upregulation of cyclooxygenase-2 gene expression elevating levels of prostaglandin E2 (186), which is involved in the initiation of inflammation and pain (187). This is from activation of EP2 receptors in the colon which transmit pain signals to the spinal cord (186). Additionally, it is theorised that 5-HT3 and 5-HT4 receptors related to serotonin are involved in the transmission of visceral sensations from the colon. Interestingly, IBS patients have elevated levels of serotonin in the gut, which may play a role in the development of symptoms. The study authors found that higher degrees of visceral hypersensitivity (pain) was linked to higher densities of nerve fibres related to another serotonin receptor, 5-HT7, in the intestinal lining (mucosa). Other studies have shown that the processing of serotonin is connected to the content of the gut microbiome, in particular the Firmicutes class of bacteria. Tachykinin, a type of molecule, interacts with NK2 or NK3 receptors NK3 to release serotonin. The NK3 receptor plays an important role in inflammation. (186)

A study of mice found that a bacterial infection compromised their gut barrier allowing food components to penetrate that barrier causing an immune response which triggered sensory nerves. Inflammatory molecules and IgE antibodies were released to tackle the infection and invasion of these food components, causing pain. Once the mice had recovered from the infection and pain subsided, introduction of the food component alone re-triggered pain via mast cell (a type of white blood immune cell) release of histamine. Pain was prevented, when attachment of histamine to sensory nerves was blocked. (144) Drugs that stabilise mast cells so they don’t release histamine, blocking IgE antibodies or blocking histamine signalling may be possibilities for new treatments. (145)

In a study, intestinal barrier changes in IBS patients correlated with both the severity and the frequency of abdominal pain (186). IBS pain can start at the beginning of a gastrointestinal infection, which causes a localised allergic reaction of the gut, using the mechanism described in the mice study above. (189)

From studies it is suggested that those with IBS have a high number of and more reactive mast cells which drives the localised allergic reaction to certain foods causing pain. This type of allergy is different from classic food allergies that can produce hives and other types of body wide reactions. (189) From a symptomatic point of view, these are known as food intolerances rather than allergies. Additionally, mast cells cover an increased area of the intestines, these cells lie in close proximity to nerve fibres and the degree of proximity to these nerve fibres relates to the severity of IBS pain. There is also an elevated concentration of substances such as histamine and proteases that activate sensory nerves in the gastrointestinal tract facilitating visceral hypersensitivity and pain. (193) Researchers at Flinders University in Australia, have correlated the intestinal pain in IBS to the itch that is induced in skin when it is irritated to cause a person to scratch in order to remove the irritant on the skin. They discuss a number of substances, receptors and processes involved in skin itch, that may also be replicated in the gut and involved in IBS pain here: (193). In discussion of future therapeutics for the “gut itch”, they describe, the researchers point to:

• improving intestinal barrier function, so that intestinal contents do not have access to:
  • immune system elements of the intestines
  • components that are part of the intestinal nervous system
  • nerve fibres that communicate with the brain
• targeting enterochromaffin cells (involved in the production of serotonin in the gut) to stop the release of mediators that interact directly with nerve fibres that communicate with the brain
• normalise levels of bile acids, 5-oxoEET, histamine and proteases
• reduce the processes by which mast cells release inflammatory substances such as histamine and proteases
• target the receptors in the lining of the intestines and the gut nervous system that interacts with the brain involved in gut irritation

(193)

Pain can be related to voltage-gated ion channels, which assist in sending electrical signals through nerves in the body. These channels open and close depending on changes across the cell membrane. Australian researchers found peptides, a type of protein, in spider venoms can inhibit voltage-gated ion channels from opening in the colon. Two peptides in tarantula venom nearly stopped visceral pain in a model of IBS by reducing sensory nerves of the colon. (194) (195)

There can be a loss of neurons (brain nerve cells) in pain control areas of the brain which may be caused by traumatic life events (176). For mild IBS pain, treatments are normally targeted at the gut. For severe IBS pain, treatments may also need to focus on the brain.

Neuroimaging involving positron emission tomography (PET) and MRI scans show pronounced differences in the activation of certain parts of the brain relating to perception and pain in IBS patients versus normal individuals – even normal gastrointestinal contractions are experienced as being painful. This proves there are differences in the way that gut stimulus is processed in the brain between those individuals and the fact that IBS is a physical problem. Interactions between the brain, central nervous system and the gut are not working properly. (127)

In a study, brain images of 55 female IBS patients were compared to those of 48 females without IBS. The IBS patients had differences in grey matter to those without IBS in significant areas related to central pain amplification and a reduction in the ability to suppress pain. The study suggested that further work was needed to identify whether genes played a role in these brain differences. (6) Another study found IBS patients have a reduction in the thickness of the insular and cingulate cortices, parts of the brain which are responsible for visceral perception (186). Additionally, an unusual pattern of activity was observed in IBS patients in the cingulate, insular, and frontal cortices, as well as in the amygdala and hippocampus parts of the brain (186). This might explain the heightened vigilance and overactive hypothalamic–pituitary–adrenal (HPA) axis, which is involved in the body’s stress response including the release of cortisol in IBS patients (186) (188).

In a study, estrogen participated in the development of the stress associated visceral hypersensitivity in female rats (70).

It is possible to have this type of pain without constipation or diarrhoea. This is known as CAPS (centrally mediated abdominal pain syndrome) or functional abdominal pain. (2) (3)

IBS Pain Links With Other Pain Disorders

Almost 60% of IBS patients also have fibromyalgia. Around 70% of fibromyalgia patients demonstrate IBS-like symptoms. Fibromyalgia results in widespread pain throughout the body caused by altered pain signalling by the nervous system. Both IBS and fibromyalgia are more common in women. Stressful life events can trigger and exacerbate both conditions. (147)

Bowel endometriosis can have similar symptoms to IBS, so it is important for symptoms to be investigated properly. Some women who had IBS as well as endometriosis had bowel symptoms that worsened during menstruation. (148)

Peptic ulcer needs to be ruled out. This normally causes pain in the upper middle part of the abdomen. (149)

IBS Pain Locations

IBS pain can occur in different parts of the abdomen, but also can exist in the mid to lower back or pelvis. Due to the variety of locations it can be confused with other conditions and conversely pain that is thought to be from IBS may be from something else. (7) (8) For example, pain in the chest or between the shoulder blades is more likely to be acid reflux/GERD. Though any chest pain should be explored by a doctor.

Pain that manifests in the lower back, may be pain referred from the intestines potentially due to constipation, gas or bloating (11):

_{^{Many of our internal organs do not have the usual pain sensors, but still have nerves that report to the brain. When the signal is from an area that the brain does not usually associate with pain the pain can be interpreted to be coming from another area usually a more superficial structure thus if you have damage or pressure on an internal organ the pain may manifest in the lower back or other location.}}

(9)

Pain in the abdomen can be from intestinal muscle contractions or an increased sensitivity to distension caused by gas. This gas may become trapped due to a deficiency in the ability to evacuate the gas. Trapped gas and spasms can refer pain to the back. IBS can also be linked to an increase in headaches, migraines, jaw and face pain due to the gut/brain access and the two way communication of pain signals between the gut and the brain. (12)

IBS Pain Timing

Some people find that their IBS pain comes on at specific times. I found this anecdotal information useful in explaining this, particularly in terms of early morning or after meal pain:

^{_{[Morning] is the time of the day the colon “wakes up” and is at its most active. This is the normal daily rhythm of the colon. It is quiet during sleep then has a burst of activity around dawn (5-7 am). This is the most active your colon will be all day. There is also a burst of activity after meals…Usually the morning burst is about 3X the activity level during the night and after meals is about 2X more active than the middle of the night…some people will tend to have after meal issues more than morning issues…}}

(5)

It stands to reason that if IBS pain is related to nerve signals being sent to the brain, that these signals will be more frequent or at greater intensity at times when the bowel is at its most active.

Psychological Therapies For IBS Pain

Mind based activities can help to close the pain gate, reduce and offer a sense of control over symptoms including:

• focused attention
• relaxation therapies
• hypnosis
• meditation
• cognitive-behavioral therapy

(1) (3)

Due to gut to brain communication often playing a role in IBS, gut-directed self hypnosis programs have shown to be effective in alleviating IBS symptoms including IBS pain. Since stress also has a contributing factor, hypnosis can place the body into a highly relaxed state thus alleviating stress. It is believed hypnotherapy acts on the unconscious mind, affecting involuntary bodily reactions normally not under a person’s control. There are no risks or side effects. (126). These programs are available through self treatment apps such as Nerva, so expensive in person appointments are not necessarily needed. Additionally, a Cognitive Behavioural Therapy (CBT) app aimed at IBS sufferers called Mahana has been launched through the NHS in the UK during 2023.

Medications For IBS Pain

There are useful guides to IBS pain medications here: (14) (10) (15) and an in-depth study here: (16), summary below:

Useful terms – An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response (18). For example, κ-opioid receptors are widely distributed in the brain, spinal cord and in peripheral tissues and have strong analgesic properties (19). This means that κ-opioid receptor agonists can help to reduce pain. Conversely antagonists blocks the action of the agonist (18)

Conventional Pain Medications Not Suitable – Paracetamol, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen and opoid drugs such as morphine have negative or lack of research data related to IBS pain. Long term use of NSAIDs can cause chronic constipation and/or be linked to IBS symptoms. IBS patients using NSAIDs may end up with compromised intestinal permeability. NSAIDS and aspirin include enteropathy, mucosal damage, intestinal strictures, ulcers, colitis and rectitis adverse effects. Narcotics such as morphine can lead to addiction. (67)

Central Neuromodulators – work across the whole central nervous system by targeting the brain. They relate to antidepressants that work on neuropathic pain at doses lower than needed to treat depression. SRIs (serotonic reuptake inhibitors) work on the availability of serotonin (5-HT). NRIs (norepinephrine reuptake inhibitors) work on the availability of norepinephrine / noradrenaline. Since these drugs work on the whole nervous system, in addition to pain relief they may have unintended consequences for other parts of the body causing side effects that may end up outweighing the benefits of the pain relief (67). The long term safety of antidepressants for non-psychiatric disorders has been questioned due to potential links with dementia, although a causal link has not been proven (81). A summary of the use of antidepressants for IBS can be found here: (120).

The main mechanism of antidepressants that inhibit neuropathic pain is first, to increase noradrenaline in the spinal cord, and second, to act on a part of the brain called locus coeruleus, which contains the greatest amount of noradrenaline. Noradrenaline helps to inhibit pain transmission. Dopamine and 5-HT also increase in the central nervous system and may enhance the inhibitory effects of noradrenaline in an auxiliary manner. (122)

The table below includes each class of central neuromodulator drug followed by their related drugs. Side effects listed may not be a complete list and may not be experienced by everyone. Consult your doctor or medicine information leaflets for the full side effects list, the correct dose and any other precautions/warnings. Note that the following have been excluded from the table:

• selective serotonin reuptake inhibitors (SSRIs) since they are not helpful for pain (119). This is most likely due to their sole activity on 5-HT receptors and lack of activity on NE receptors (117)
• tetracyclic antidepressants (mirtazapine, mianserin & trazodone) are mentioned in relation to treatment of early satiation, weight loss, and chronic nausea/vomiting rather than pain (16)
• Aminoketones such as Bupropione lack evidence for gut/brain disorders (16)

The following tables compare the level of activity each drug has on each type of receptor (68):

Receptor activity and dosages for TCA antidepressants (68)

Drug	NE	5-HT	H1	ACh	Initial Dose	Dose Range
Amitriptyline	+2	+2	+4	+4	10–50	25–150
Imipramine	+2	+2	+4	+2	10–50	25–150
Desipramine	+4	+2	+1	+1	10–50	25–150
Nortiptyline	+3	+2	+2	+2	10–50	25–150

Tricydic antidepressant neurotransmitter activity (118).

Drug name	Trade name	ACh	Hist	5-HT	NE	Dop	Sedation	Comments
Amitriptyline	Elavil	+++	++	+++	++	–	+++	Commonly used for sleep disorder
CLomipramine	Anafranil	++	++	+++	+++	–	+++	Commonly used for OCD
Imipramine	TofraniL	++	++	+++	++	–	++	Used for nocturesis
Doxepin	Sinequan	+++	+++	++	+	–	+++
Desipramine	Norpramin	+	+	–	+++	–	+
Nortriptyline	Aventyl	++	+	++	++	–	++	Less hypotension than other TCAs

Receptor activity and dosages for SSRI and SNRI antidepressants (68)

Drug	NE	5-HT	ACh	Initial Dose	Dose Range
Duloxetine	+4	+4	–	20–40	20–80
Venlafaxine	+4	+3	–	25–50	25–150

Efficacy of pain relief for each drug type The “number needed to treat” (NNT) is an index used to compare the efficacy of medications based on the results obtained in a variety of
clinical studies (meta analysis) and is represented as the number of patients treated for whom pain was reduced by up to 50%, with a smaller numerical value indicating a stronger efficacy. (122):

• The NNT of dual-type TCAs (e.g., amitriptyline, imipramine, clomipramine), which inhibit reuptake of both noradrenaline and 5-HT, is 2.1
• The NNT for noradrenaline reuptake inhibitors (nortriptyline, desipramine) is approximately 2.5
• The NNT for SNRI is 5.0
• The NNT for SSRI is 6.8. SSRIs are not recommended for the treatment of neuropathic pain, though they are popular drugs for the treatment of depression. Noradrenaline plays a more important role in the inhibition of neuropathic pain, rather than 5-HT, but simultaneous administration of noradrenaline and 5-HT selective reuptake inhibitors in an animal experiment produce a combined analgesic effect, suggesting that 5-HT has auxiliary actions.

(122)

Peripheral Neuromodulators – targets electrical impulses elsewhere in the body and not the brain. The table below includes each class of peripheral neuromodulator drug followed by their related drugs. Side effects listed may not be a complete list and may not be experienced by everyone. Consult your doctor or medicine information leaflets for the full side effects list, the correct dose and any other precautions/warnings.

Class	Comments
Antispasmodics (anticholinergics) Action Anticholinergics selectively blocking the binding of acetylcholine to its receptor in nerve cells. Acetylcholine causes involuntary muscle movements in the lungs, gastrointestinal tract, urinary tract, and other areas of the body. (17) Side Effects Blurred vision, dry mouth, dry eyes, decreased urine production, decreased sweat production constipation, memory impairment, delirium, confusion (24)	– avoid in the elderly because side effects are particularly common and problematic in older individuals (24) – the purpose of anticholinergics in IBS is to reduce intestinal spasms – anticholinergics reduce but do not abolish peristalsis (wave like intestinal movements that push contents forwards) (22), so there is a risk of constipation and are best used for IBS-D rather than IBS-C (23).
Drug Names	Comments
Mebeverine (Colofac®) (14) IBS Type: IBS-D Dose Standard-release tablets (135mg): the usual dose is 1 tablet, taken 3 times a day Slow-release capsules (200mg): the usual dose is 1 tablet, taken twice a day (25)	– musculotropic [acting on muscle tissue] agent that reduces intestinal peristalsis (14)
Hyoscine butylbromide (Buscopan® / Buscapina®) (14) IBS Type: IBS-D Dose The usual dose for symptoms of IBS diagnosed by a doctor in adults and children aged 12 years and over is 1 tablet taken 3 times a day. (26)	– antispasmodic medication for relieving abdominal discomfort and pain due to cramps and spasms. (May require a physician’s prescription in some countries.) – over-the-counter (14)
Peppermint Oil – Enteric Coated (Pepogest® / Colpermin®) (14) – Sustained Release formula (IBgard®) IBS Type: IBS-D/C Dose For Pepogest take 1 softgel three times daily with water, 30 to 60 minutes before food. Discontinue use if heartburn occurs*. *Peppermint oil is used to relax the ileocecal valve which sits between the stomach and the throat to gain access to the small intestine in some medical procedures (169). The relaxation effect on this valve could contribute to GERD since the valve isn’t tight enough to stop stomach contents flowing back. This is why the enteric coating is important to deliver peppermint oil straight to the intestines.	– also has analgesic effects by containing L-menthol which is a κ-opioid receptor agonist and 5-hydroxytryptamine (HT)3 receptor antagonist (16) – note that 5-HT3 receptor antagonists slow transit and 5-HT4 receptor antagonists speed transit (16); this suggests that peppermint might slow transit – relieves abdominal cramp, spasms and bloating of IBS – over-the-counter (14) – don’t take antacids at the same time as peppermint oil capsules since they can make the capsule break down causing reflux; always swallow whole and not chew them (170) – reviews of peppermint oil here – IBgard® has patented SST (Site-Specific Targeting) to deliver peppermint oil beyond the stomach – it is best taken 30 mins to 1 hour before eating otherwise the coating may get broken down leading to reflux – reviews of IBgard here and here
Pinaverium Bromide (Dicetel®) (113) IBS Type: IBS-D/C Dose 50 mg, taken 3 times a day with a glass of water during meals or snacks. Your doctor may increase the dose to 100 mg 3 times daily if adequate relief is not obtained with the lower dose. The tablet should not be swallowed when lying down or just before bedtime. The recommended maximum (total) daily dose of pinaverium is 300 mg. (177)	– a calcium channel blocker (113) – relaxes the colon and intestines – inhibits colonic motility in response to food (113) – exhibits very weak anticholinergic effects – minor side effects epigastric pain and/or fullness, nausea, constipation, heartburn, distension, diarrhoea, headache, dry mouth, drowsiness, vertigo and skin allergy (113). Isolated cases of severe esophagitis (115). – helps to treat diarrhoea, constipation and pain (114) – Dicetel reviews here
Hyoscyamine Sulfate (Anaspaz® / Levsin®/ Levbid® / Nulev®) (14) IBS Type: IBS-D/C Dose Anaspaz tablets and liquid are usually taken three or four times a day.	– antispasmodic medication for relieving abdominal discomfort and pain due to cramps and spasms (14) – prescription only – Reviews here
Phenobarbital, Hyoscyamine sulfate, Atropine Sulfate, Scopolamine Hydrobromide (Donnatal®) (14) IBS Type: IBS-D/C Dose One or two Donnatal® Tablets three or four times a day according to condition and severity of symptoms.	– slows the natural movements of the gut by relaxing the muscles in the stomach and intestines and acts on the brain to produce a calming effect. – prescription only (14) – Donnatal reviews here
Dicyclomine Hydrochloride / Dicycloverine Hydrochloride (Bentyl® / Bentylol®)(14) IBS Type: IBS-D/C Dose The recommended initial dose for Bentyl is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued.	– antispasmodic which relieves smooth muscle spasm of the gastrointestinal tract (May be over the counter in some countries.) (14) – prescription only – Dicyclomine reviews here
Chlordiazepoxide, Clidinium (Librax®) (14) IBS Type: IBS-D/C Dose The dosage should be individualized for maximum beneficial effects. The usual maintenance dose is 1 or 2 capsules, 3 or 4 times a day administered before meals and at bedtime.	– a benzodiazepine which reduces stomach acid and decreases intestinal spasms. (14) – prescription only – Librax reviews here
Trimebutine Maleate (Modulon®) (14) IBS Type: IBS-D/C Dose The adult recommended dose is up to 600 mg daily in divided doses. It is administered as one 200 mg tablet three times daily before meals.	– regulates abnormal intestinal activity. – prescription only (14)
Clidinium, Chlordiazepoxide, dicyclomine (Normaxin®) (14) IBS Type: IBS-D/C	– helps relieve, prevent and lower the incidence of muscle spasms, particularly the smooth muscles of the bowel wall. – prescription only (14)
Methscopolamine Bromide (Pamine® / Pamine Forte®) (14) IBS Type: IBS-D/C Dose The average dosage of Pamine® Tablets is 2.5 mg one-half hour before meals and 2.5 to 5 mg at bedtime. A starting dose of 12.5 mg daily will be clinically effective in most patients without the production of appreciable side effects.	– slows the natural movements of the gut and relaxes the muscles in the stomach/intestines. – prescription only (14) – Methscopolamine reviews here
Alverine Citrate (Spasmonal®) (14) IBS Type: IBS-D/C Dose The usual dose is 1 or 2 capsules taken up to 3 times a day.	– relaxes the muscles in the intestine (gut). – prescription only (14)
Class	Comments
Guanylate Cyclase-C Receptor Agonists Action Stimulate the guanylate cyclase-C (GC-C) receptor to produce of cyclic guanosine monophosphate (cGMP). cGMP alters the conduction properties of nociceptive (pain perception) neurons located in the submucosa (tissue beneath the muscous membrane in the gastrointestinal tract). This has the effect of calming intestinal nerves. (16) Side Effects Linaclotide: Common: diarrhoea, stomach pain Less common: heartburn, loss of appetite, nausea, vomiting, weakness (27) Plecanatide: Diarrhoea is the most common side effect (28)	– since cGMP also stimulates excretion of fluids which in turn speeds up gut transit, they are only suitable for patients with IBS-C – pain reduction occurs gradually over 2 months with a bit less than half of those studied reaching pain reductions of 30% or more (16)
Drug Names	Comments
Linaclotide (Linzess® / Constella®) (14) IBS Type: IBS-C Dose 290 micrograms once daily	– advised to take 30 minutes before a meal. However, some have found experimentation with the timing is needed to get the best response (e.g. one or two hours before eating or at night on an empty stomach) – patient feedback on this here, here and here. – 4 weeks to see partial improvements in pain and bloating with maximum effects at 10 weeks (62) (64) – discontinue use if no effects at week 12 (62) (64) – if there is a partial response, efficacy doesn’t significantly increase from doubling the dose. (62) – after week 12 of stopping patients may see their symptoms return to previous levels. Re-starting may take 4-10 weeks to achieve pain relieving effects again (62) – treatment is required for 6-12 months with the possibility of considering stopping with enough time for a therapeutic effect (62) – increasing cGMP has other benefits in suppressing intestinal carcinogenesis and improves the barrier function of the colon (63) – advantage of being metabolised locally in the gastrointestinal tract and minimally detected in blood stream at recommended dose (65) – Linaclotide reviews for IBS-C plus here and here
Plecanatide® (14) (Trulance®) (14) IBS Type: IBS-C Dose 3 mg taken orally once daily	– Plecanatide reviews for IBS
Class	Comments
Chloride Channel-Related Action – acts on CIC-2 chloride channels drawing water into the intestines to accelerate transit (81) Side Effects Nausea, diarrhoea, abdominal distension, headache, abdominal pain	– prime target is to draw in water and seems to be less efficacious for pain relief (178)
Drug	Comments
Lubiprostone (Amitiza®) (14) IBS Type: IBS-C Dose 8 mcg twice daily (81)	– in a study it reduced abdominal pain, straining, and improved stool consistency, but had no significant effect on quality of life. Nausea was the commonest side effect, experienced by 8% of patients. (81) – Lubiprostone reviews for IBS
Class	Comments
Sodium-Hydrogen Exchanger (81) Action – inhibitor of the gastrointestinal sodium/hydrogen exchanger, NHE3, which results in increased intestinal sodium and water excretion (81) Side Effects Diarrhoea (81)	– action by fluid retention to soften stools (179) – reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain (179)
Drug	Comments
Tenapanor IBS Type: IBS-C Dose 50 mg twice a day (81)	– in a study improved stool transit, pain, discomfort, bloating, cramping, and fullness (81) (129) (130) – approved by FDA in 2019 for IBS-C – Tenapanor IBS Reviews
Class	Comments
Peripheral Opioid Receptor Agonists/Antagonists (81) Action Stimulate the visceral μ (opioid) receptor which reduces diarrhoea (81) Side Effects Constipation, feeling sick, headaches, wind (29)
Drug Names	Comments
Loperamide (Imodium®) (14) IBS Type: IBS-D Dose Capsules or tablets: take 2 capsules or tablets, taken immediately. Then take 1 capsule or tablet after each runny poo.	-longer term use of loperamide can cause constipation and/or abdominal pain – slows down the movement of fluid through the intestines (14) – never take Imodium if you have abdominal pain without diarrhoea. Imodium is not approved to treat abdominal pain without diarrhoea. Depending on the cause of your pain, taking Imodium could make the pain worse. (31)
Eluxadoline (Viberzi® / Truberzi®) (81) (14) IBS Type: IBS-D Dose 100 mg twice a day (30)	– has agonistic properties on μ- and κ-receptors, and antagonistic properties on δ-receptors and has been shown in animal studies to reduce pain and normalise transit over a wider dose in IBS-D patients than loperamide. (16) – IBS-D patient study showed significant elevation in pain threshold (70) – warnings for increased potential for pancreatitis and is contra-indicated in those who have had a cholecystectomy or previous or current liver disease. (16) – Eluxadoline reviews for IBS
Fedotozine (discontinued)	– in a trial, significantly reduced pain sensation (70) but development discontinued and it was never marketed (85)
Buprenorphine (ORP-101®) (14) IBS Type: IBS-D	– a buprenorphine dimer therapeutic, is a peripherally active partial mu opioid receptor agonist and K opioid receptor antagonist designed to ease colonic hypersensitivity stemming from intestinal hyperalgesia and motility dysfunction in IBS-D. (14) – Phase 2 IBS-D study positive but associated company no longer in existence.
Class	Comments
5-HT4 Serotonin Receptor Agonists (81) Action Accelerate transit (16) Side Effects Diarrhoea, cramping, cardiovascular issues with “old generation” drugs in this class (81)
Drug Name	Comments
Prucalopride (Motegrity® / Resolor® / Resotran® / Prudac® / DuphaPro®) (14) IBS Type: IBS-C Dose 2 mg per day (16)	– a selective 5-HT4 agonist – phase III trials on the 2 mg per day dose of this drug in women found large or moderate positive effects on abdominal pain and discomfort, bloating, and painful bowel movements (16) – common side effects: diarrhoea, stomach pain (32) – Prucalopride reviews for Chronic Idiopathic Constipation
Tegaserod (Zelnorm®) (14) IBS Type: IBS-C Dose 6 mg twice daily (84)	– in a study significantly reduced sensitivity to rectal distension and visceral sensation (70) – side effects here – In 2007, Zelnorm was withdrawn from the U.S. market due to a higher chance of heart attack, stroke, and unstable angina (heart/chest pain). In 2019 it was reintroduced after a safety review but only to females with IBS-C under age 65 (83) – Tegaserod reviews for IBS
Class	Comments
5-HT3 Serotonin Receptor Antagonists (81) Action Slows transit (16). 95% of serotonin in the body resides in the gut. 5-HT3 receptors respond to serotonin produced by enterochromaffin (EC) cells in the gut and send signals encoding pain to the central nervous system. Serotonin transporter or SERT is key to the absorption of serotonin. IBS patients have been found to have a decrease in SERT cells lining the bowel, which causes serotonin to hang around for longer. (20) Reduced SERT activity could contribute to visceral hypersensitivity through increased 5-HT/serotonin availability. (21) Side Effects Constipation, nausea, abdominal pain, headache, fatigue, malaise, bloating, muscle spasm, cough, piles (33)
Drug Name	Comments
Alosetron (Lotronex®) (14) IBS Type: IBS-D Dose 0.5 mg twice a day (16)	– has been shown to improve abdominal pain, discomfort, and bloating in female IBS-D patients – careful prescribing of 0.5 mg BID helps avoid serious side effects of the drug including severe constipation and ischemic colitis (16) – Alosetron is not available in the UK – it was withdrawn because of severe constipation (in 25% of people taking Alosetron) (82) – Alosetron reviews for IBS
Ramosetron (IBset® / Nasea® / Nozia® / Irribow®) (14) IBS Type: IBS-D Dose 2.5 μg once daily (34)	– approved for the treatment of men and women with IBS-D in Asia whilst assisting with abdominal pain and discomfort (16)
Ondansetron (Zofran, Zofran ODT, Zuplenz) (Bekinda®) (14) IBS Type: IBS-D	– may have no benefit over placebo in terms of abdominal pain (81)
SMP-100 (14) IBS Type: IBS-D	– SMP-100 is a selective serotonin receptor-3 (5-HT3) partial agonist that has a large therapeutic index, better side-effect profile, and the potential to treat a wider spectrum of IBS-D and IBS-A patients. (14)
The following are not routinely prescribed for IBS pain and/or have been experimental – some are central and some peripheral acting
Class	Comments
Delta Ligand Agents (16) Action Have wider reaching pain effects through their blockage of the α2δ subunit of voltage-sensitive calcium channels on neurons (16). Their binding potently to an auxiliary protein associated with voltage-gated calcium channels, reduces depolarization-induced calcium influx at nerve terminals and reduces the release of several excitatory neurotransmitters, including glutamate, noradrenaline, substance P, and calcitonin gene-related peptide (CGRP), which are involved in pain mechanisms (81). Side Effects Headaches, feeling sleepy, tired or dizzy diarrhoea, mood changes, feeling sick, swollen hands, arms, legs and feet, blurred vision, for men, difficulties with getting an erection, weight gain – because pregabalin can make you feel hungry, memory problems (35)	– limited evidence of these drugs such as pregabalin being useful for IBS pain (16) (118) – like central neuromodulators, they are wider reaching, which may result in unintended side effects (67) – There are insufficient data in the preliminary report to assess safety in IBS patients. In the fibromyalgia literature, pregabalin, >300 mg dose, has been associated with somnolence, dizziness, and >7% weight gain in an analysis of 5 trials with 3808 patients (81).
Drug Name	Comments
Pregabalin (Lyrica®) (14) IBS Type: IBS-D/C Dose 225 mg twice daily (36) Initiated at 50 mg three times daily for 3 days then titrated up thereafter by 50 mg three times daily every 4 days leading to 200 mg three times daily (54). A preliminary report of a randomized, controlled clinical trial of pregabalin, 225 mg, in 85 patients with IBS reported lower average pain scores during weeks 9–12, and average symptom severity scores were lower with pregabalin than placebo (81).	– limited evidence for IBS pain (16) – should only be tried when better studied medications have failed (54) – pregabalin has higher bioavailability than gabapentin (90% versus 33-66%) and is rapidly absorbed (peak: 1 hr versus peak: 3 to 4 hours) meaning efficacy may be seen at lower doses which may mean fewer side effects. Plasma concentration rise linearly with increasing dose whereas gabapentin doesn’t (59) – reviews including side effects here (60) (61), some experienced much longer after the last dose – also see below regarding gabapentin which may be similar to Pregablin in some respects
Gabapentin (Neurontin) (81) IBS Type: IBS-D/C Dose 100 mg three times daily for 3 days then 200 mg three times daily (54) Forty patients with IBS-D were randomized for a 5-day period to treatment with gabapentin, 300 mg/day and then 600 mg/day; rectal sensory thresholds were increased through attenuating rectal sensitivity to distension and enhancing rectal compliance (81). Do not take antacids within 2 hours of taking gabapentin, as antacids reduce the body’s ability to absorb the drug. This includes Magnesium Oxide used for IBS-C. (123)	– limited evidence for IBS pain (54) – should only be tried when better studied medications have failed (54) – dose is started low and can be reverted back to the previous dose for longer if side effects are intolerable (55) – needs to be at the alpha-2-delta receptor for 17-20 hours to be effective which means it needs to be taken around the clock rather than an as needed basis (55) – see comparison to pregabalin above – withdrawal symptoms can be experienced at as little as 400mg/day when stopped after 3 weeks. Withdrawal symptoms can be for 10 days or much longer including changes in mental status, chest pain, high blood pressure. (56), (57). I experienced stabbing stomach pains for 3 months after stopping gabapentin after taking a low dose only for a short period – there is anecdotal evidence of this symptom here (58). – needs to be tapered and not stopped immediately – the brain gets used to enhanced GABA when taken for a long period (124)
Class	Comments
Antihistamines (70) Action Histamine-1 receptor antagonists (70) Histamine impacts the TRPV1 pain receptor (72) Side Effects Headache, dry mouth, nausea, drowsiness, blurred vision, difficulty peeing, (for ones that make you drowsy) (69) A study found 3.5 times the risk of gliomas, a common type of brain tumour in patients with long-term antihistamine use for allergic conditions. (146)	– IBS patients have significantly increased histamine-1 receptors in intestinal and colonic mucosa (70) – Mucosal release of histamine and tryptase, initiate mast cells which play a key role in inflammation and contribute to activation of visceral pain pathways (70)
Drug Name	Comments
Ebastine (71) IBS Type: IBS-D/C Dose 20 mg per day (71)	– In a study 20g per day achieved considerable pain relief at week 12 (71) (72) (80) – does not significantly penetrate blood brain barrier (73) – effective block of histamine-1 receptor peripherally, so low incidence of central effects (drowsiness) (73) – has a favourable safety profile (73) – usually well tolerated (79) – potential for headache, sleepiness, and dry mouth
Ketotifen (74) IBS Type: IBS-D/C Dose Adults: one tablet (1 mg) twice daily (75)	– may cause irritability or nervousness, feeling dizzy or sleepy, disturbed sleep, dry mouth (75) – in a study increased pain thresholds and reduced IBS symptoms (76)
Fexofenadine IBS Type: IBS-D/C Dose 120mg once a day for adults and children aged 12 years and over (78)	– may cause feeling sick (nausea), feeling sleepy, headaches, dry mouth, feeling dizzy (78) – reversed post stress visceral pain in an animal study (77)
Class	Comments
Transient Receptor Potential Vanilloid Type I (TRPV1) Antagonists (70) Action – Reduces TRPV1 pain receptor activity (70) Side Effects See comments below	– levels of TRPV-1 are elevated in patients with rectal hypersensitivity (70)
Drug	Comments
Capsazepine (70) Qutenza® (86) IBS Type: IBS-D/C Dose – transdermal application using patches (under the supervision of a physician) (86) – for peripheral neuropathic pain (86) – Up to 4 patches applied to intact, non-irritated, dry skin, and allowed to remain in place for 30 minutes. (87)	– must only be applied by a healthcare professional (87) – can cause a mild burning sensation that can last for several hours or days. (87) – may be repeated every 90 days, as warranted by the persistence or return of pain (88)
Class	Comments
Anti-inflammatory Drugs (70) Action – reduce intestinal immune cells which play a role in visceral pain (70) Side Effects Common side effects: indigestion, stomach pain or wind, feeling or being sick (nausea or vomiting), diarrhoea, headaches, muscle aches and pains (89)	– inflammatory mediators, including neuropeptides, cytokines, and prostanoids are involved in visceral pain (70) – gut levels of prostaglandin E2 & immune cells, including CD25+ T cells were elevated in the intestinal mucosa of patients with IBS (70) – mRNA expression of the pro-inflammatory mediator, IL-1β, has been reported in patients with post-infectious IBS (70) – have been shown to alleviate pain perception in IBS but only in experiments (70) – these class of drugs are prescribed for inflammatory bowel disease (Chron’s & colitis) (89)
Drug	Comments
Mesalaxine / Mesalamine (5-aminosalicylic acid) (70) IBS Type: IBS-D/C	– experimental in IBS only – a systematic review found Mesalamine to be more effective than placebo for global IBS symptoms but not for abdominal pain or bowel habit or stool frequency (180). – conversely a randomized double-blind placebo-controlled study to evaluate the effect of long-acting mesalamine on postinfectious irritable bowel syndrome with diarrhoea found Mesalamine to be effective in reducing IBS symptoms and improving quality of life (181).
Class	Comments
Toll-like Receptor (TLR) Antagonists (70) Action – reduce TLR activity involved in visceral pain (70) Side Effects See below comment	– in post infectious IBS, TLR9 modulates immune reactions to bacteria and encodes defense proteins in the epithelial barrier (70) – TLRs associated with immune responses related to stress in visceral pain patients (70)
Drug	Comments
TAK-242 (70) (Resatorvid) IBS Type: IBS-D/C	– antagonist of TLR4, suppressed visceral pain induced by chronic stress (70) – experimental only – underwent trial for the the treatment of severe sepsis which resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated (97)
Class	Comments
β2-adrenergic Receptor Antagonists (70) Action – reduce β2-adrenergic receptor activity – β-adrenergic receptors related to stimulation of electrogenic K+ currents with significant roles in colonic perception (70) – blocks norepinephrine involved in chronic stress which plays a role in visceral hypersensitivity (90) Side Effects Feeling tired, dizzy or lightheaded (these can be signs of a slow heart rate), cold fingers or toes (beta blockers may affect the blood supply to your hands and feet), difficulties sleeping or nightmares, feeling sick (91)	– these drugs are normally prescribed as beta-blockers – animal study only
Drug	Comment
Propranolol	– reduced, intermittent, stress-induced visceral hypersensitivity in rats (70) – animal study only
Class	Comment
Glutamate Receptor Antagonists (70) Action – glutamate is an excitatory neurotransmitter (makes neurons more likely to fire) in the central nervous system (70) – N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) are the binding receptors of glutamate (70) – NMDA & AMPA are involved in pain perception (70) – acts as antagonist of glutamate AMPA receptor (70)	– experimental only (70)
Drug	Comments
6-cyano-7-nitroquinoxaline-2,3-dione disodium salt	– alleviated visceral perception induced by substance P in experiments (70)
Class	Comments
Cannabinoid Receptor Agonists (70) Action – Cannabinoid (CB2) receptors located in the gastrointestinal tract are involved in mitigating gut motility and pain perception (70)	– Cannabinoid (CB1) receptors are linked with catalepsy and hypothermia (70) – selective CB2 receptor agonists have no adverse effect on cannabinoid pathways related to CB1 receptor, so can be considered safe potential drugs for managing visceral pain (70)
Drug	Comments
RQ-00202730	– alleviated visceral pain stimulated in an animal model of IBS (70) – however development discontinued due to disappointing results in Phase II clinical trials
PF-03550096	– alleviated visceral pain stimulated in an animal model of IBS (70)
APD371 (Olorinab®)	– Full agonist of the cannabinoid type 2 receptor (CB2) in development for visceral pain. Phase 2b CAPTIVATE clinical trial (NCT04043455) is located here. – However this trial did not achieve expected results – story here.
Class	Comments
Protease-activated Receptor agonists (70) Action – proteases participate in pain perception by affecting protease-activated receptors (PAR) of which there are 4 main ones PAR1 to PAR4 – these are able to conduct or block pain sensation (70)	– PAR4-deficient animals experienced more induced colonic pain (70) – agonists of PAR4 help control visceral pain by suppression of free intracellular calcium mobilization which is stimulated by the pain promoting PAR2 agonists (70) – PAR1 has the ability to block pain sensation (70) – Antagonizing PAR2 receptors as well as activation of PAR1 and PAR4 receptors by selective agonists can be considered as new therapeutic targets for managing IBS visceral pain (70) – animal models only
Drug	Comments
AYPGKF-NH(2)	– a PAR4 agonist, which alleviated the visceromotor response to colorectal distension in mice (70) – animal models only
Class	Comments
Tyrosine Receptor (Trk) Antagonists (70) Action – TrkA is mainly expressed in pain sensory neurons (70) – TrkA is significantly elevated in patients with rectal hypersensitivity and faecal urgency (70)
Drug	Comments
k252A	– significantly reduced visceral hypersensitivity to colorectal distension induced by chronic stress-induced in mice (70) – animal study only
Class	Comments
Calcium Channel Antagonists (70) Action – elevation of the current density in the T type calcium channel (a subfamily of voltage-gated calcium channels) within colonic pain receptors can exacerbate visceral pain (70)
Drug	Comments
Mibefradil (70)	– inhibit butyrate-induced visceral pain in rats (70) – animal study only – drug used for used for the treatment of hypertension and chronic angina pectoris, voluntarily pulled from the market due to serious health hazards and drug interactions
Ethosuximide (182) (an antiepileptic drug)	– inhibit butyrate-induced visceral pain in rats (70) in an animal study – IBS patients showed a significant decrease in pain when compared to Mebeverine (antispasmodic) in a small human trial (182)
NP078585 (70)	– inhibit butyrate-induced visceral pain in rats (70) – animal study only
Class	Comments
Sodium Channel Blockers Action – sodium channels are implicated in visceral sensation (70)	– involves some promising studies
Drug	Comments
Lidocaine (70)	– in a clinical trial, the intra-rectal injection of lidocaine, increased pain threshold and mitigated rectal hypersensitivity in patients with IBS (70) – Lidocaine patches are used for managing localized neuropathic pain. One to 3 patches can be used at the same time for up to 12 hours. They have a low risk of side effects. (125) – reviews here and here (some people experienced side effects including racing heart and elevated blood pressure)
A-803467 (70)	– in a study could reduce pain sensitivity in visceral tissues (70)
Ambroxol	– produced a reduction in inflammatory pain in rats (70)
Vixotrigine	– By targeting the PN1/Nav1.7 sodium ion channel, pain signals would not be transmitted. Does not involve the central nervous system so no side effects and no addictive qualities. (162) (163) – Trial failed due in part to difficulties in designing molecules that can block just Nav1.7 and not closely related ion channels that play critical roles outside pain sensing. (164)
Class	Comments
Neurokinin (NK), a Tachykinin peptide, Antagonists (70) Action – NK receptors as well as substance P (another Tachykinin) affect sensory neurons and are involved in pain sensation (70)
Drug	Comments
SR-140333	– selective antagonists of NK1 receptors (70) – in live studies reduced inflammatory associated pain sensitivity (70)
MEN-10930	– selective antagonists of NK1 receptors (70) –  in live studies reduced inflammatory associated pain sensitivity (70)
Ibodutant (95) IBS Type: IBS-D Dose 10 mg once daily (96)	– selective antagonists of NK2 receptors (95) – went to Phase 3 clinical trials since Phase 2 study showed improved abdominal pain and stool pattern in IBS-D in females, but not in males (95) – Phase 3 trial discontinued due to unfavourable results (96)
Nepadutant (70)	– selective antagonists of NK2 receptors (70) – in animal studies shown to significantly modulate the colorectal hypersensitivity to distension (70) – did not go to market
Saredutant (70)	– selective antagonists of NK2 receptors (70) – in animal studies shown to significantly modulate the colorectal hypersensitivity to distension (70) – made it to Phase III clinical trials as an antidepressant and a anxiolytic (anti-anxiety agent), however further research ceased
SR-142801 (70)	– selective antagonists of NK3 receptors (70) – peripheral administration suppresses inflammatory associated visceral pain (70)
Talnetant (SB-223412) (70)	– selective antagonists of NK3 receptors (70) –  2007 study showed no significant improvement in rectal hypersensitivity over placebo – use as a potential antipsychotic drug for the treatment of schizophrenia also discontinued
Class	Comments
QRFSR peptide (156) Action – stops the normal breakup of enkephalins, natural pain-killing opioids in the spinal cord (156) – only acts where there’s a painful stimulus unlike morphine which fixes to multiple receptors, risking side effects (157) Side Effects – stronger pain relief than morphine without the side effects of morphine such as dependence and constipation (156)	– a peptide naturally produced by the human body and first isolated from human saliva (156) (157)
Drug	Comments
Opiorphin – stable form STR-324	– general pain relief not specific to IBS. May become of importance for neuropathic pain relief. (157) – clinical trial investigated dosing safety only (158) (159)
Class	Comments
HCN2 blockers Action – HCN2 initiates electrical signals in pain sensitive nerves causing continuous pain – blocking HCN2 gives pain relief (160) (161) Side Effects – animal studies have shown blocking of HCN2 provides pain relief without side effects (160)	– funding allocated to develop a pain relief drug related to the finding concerning HCN2 (160) (161)
Class	Comments
microRNA-21 Antagonists Action – blocking the release of microRNA-21 in the dorsal root ganglion (DRG) of the brain which is released after nerve injury and taken up by surrounding immune cells, ultimately leading to local inflammation and neuropathic pain. (165)	– had an anti-inflammatory effect at a cellular level, which prevented neuropathic pain from occurring in mice. The advantage of this method is that these particles, containing agents that block microRNA-21, do not infiltrate the brain and lead to side effects. (165)

Combination Therapies – by combining different medications is may be possible to maximise effectiveness with minimising side effects. (68)

Options for combining treatment modalities in augmentation therapy (68)

Combination	Examples
Central drug with central drug	SSRI with TCA
	SNRI with SSRI
Central drug with peripheral drug	SSRI with anticholinergic
	TCA with pregabalin or gabapentin
Non-pharmacological treatment with central drug	Hypnosis with TCA
	CBT with SSRI
Non-pharmacological treatment with peripheral drug	Hypnosis with anticholinergic
	CBT with pregabalin or gabapentin
Central drug with non-pharmacological treatment and peripheral drug	Hypnosis with SSRI and anticholinergic agent
	CBT with SNRI and pregabalin

Alternative Treatments For IBS Pain

Probiotics – Visceral hypersensitivity can be caused by gut inflammation suggesting that probiotics that help with inflammation might also reduce visceral hypersensitivity (41). The following table discusses probiotics studied in this area:

Probiotic	Comments
Bifidobacterium and Lactobacillus	– independently and in mixture reduced intestinal permeability as well as the contractile response of colonic smooth muscles in mice with IBS (70) – significantly reduced visceral pain symptoms of post-infectious IBS in animals by suppression of intestinal inflammation and release of inflammatory cytokines (70)
L. paracasei	– inhibited visceral hypersensitivity in healthy mice that had inflammation caused by bacterial disturbances from antibiotics, through it’s anti-inflammatory effects and inhibition of Substance P (42), which is increased by antibiotics. In general, IBS mucosal biopsies have shown increased Substance P, a neurotransmitter and a modulator of pain perception by altering cellular signalling pathways and increased Transient Receptor Potential Vanilloid 1 receptor (TRPV1) positive fibres, which are associated with pain. (41)
L. acidophilus	– inhibited of visceral sensitivity equivalent to that of morphine 0.1 mg/kg through increased the expression of μ-opioid and cannabinoid receptors in normal animals, independent of an anti-inflammatory effect. (41)
Bifidobacterium infantis	– decrease in pain/discomfort with 100 million CFU/day dose (41) – the gut microbiota may influence symptoms in IBS, with lower numbers of bifidobacteria associated with higher pain scores in IBS (116)
Liquid non-dairy probiotic product containing  Lactobacillus rhamnosus,  Lactobacillus plantarum,  Lactobacillus acidophilus, and Enterococcus faecium	– decrease in abdominal pain in a randomized, double-blind, placebo-controlled clinical trial on moderate to severe IBS patients (70)
Blautix	– single-strain bacteria that consumes gases which are known to cause bloating, pain and other IBS symptoms (183) – In a phase II trial, Blautix demonstrated signals of clinical activity in both IBS-C and IBS-D patients (184)

Curcumin – has been shown to manage visceral hypersensitivity, believed to be due to its action on the 5-HT1A receptor and decrease visceromotor response to colorectal distension in rats. Curcumin, at least in part, interacts with TRPV1. (70) It also has anti-inflammatory, anti-oxidative and anti-proliferative (used or tending to inhibit cell growth) properties. It increased the bacterial diversity in mice which would have a beneficial effect on tumorigenesis (the production or formation of a tumour or tumours). (98). There is a discussion regarding BCM-95 Vs Meriva Curcumin products here (99). There seems to be controversy around the efficacy of curcumin discussed here: (100).

Berberine – was shown to reduce visceral hypersensitivity in rats (70) (101). In a further study, it prevented stress-induced gut inflammation and visceral hypersensitivity and reduced intestinal motility in rats (102).

Ginseng – In a trial of IBS patients conducted for sixty days who took dry extract of Panax ginseng (300 mg/day) specifically, it was found that Panax ginseng helped to control abdominal pain. It is thought that this is due to its action on pain related calcium and sodium channels and on sensory neurons. (103) Although a natural product, there are potential side effects of ginseng including headaches, sleep problems, digestive problems, changes to blood pressure and blood sugar, diarrhoea, menstrual problems, dizziness, rapid heartbeat and severe skin reaction. It is not recommended during pregnancy. (104) (105) Some experts suggest you shouldn’t use it for more than 3 months or sometimes just a few weeks at a time. (106) Elsewhere it says that Panax ginseng is likely safe when taken for up to 6 months, but possibly unsafe when taken for more than 6 months, since it may have some hormone-like effects that could be harmful with long-term use. (107)

Dicentrine – is a plant derived compound that acts as a α adrenoceptor antagonist and had been shown to reduce visceral hypersensitivity in an animal study (70). It’s use seems to be experimental since it is not available for sale.

JCM-16021 – is a chinese medicine consisting of 7 herbal components containing Tetrahydropalmatine which comes from the Corydalis plant. It has been shown to reduce visceral pain in animal studies. (70) A small scale clinical trial for IBS-D patients (108) (109), showed it to be potentially effective in improving symptoms of IBS-D (185).

St Johns Wort – a study concluded that St Johns Wort, a natural remedy, did not clearly improve IBS symptoms including pain. (44)

Melatonin – In a study, melatonin 3 mg at bedtime for two weeks significantly reduced abdominal pain and rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles. (128)

Silicol^®gel – a treatment for abdominal discomfort. However, the product contains silicon dioxide and there have been some concerns raised over its safety. (4)

Heat – A study found that heat treatment or more than 40C (104F) applied to the skin near internal pain can switch on heat receptors where the pain is felt which block the body’s ability to detect pain (51). Homefront have a range of good quality electric heating pads with automatic 90 minute shutdown timers for your safety. Some heat pads are wearable so they can be strapped with the heat at the back or the front (abdomen) such as this one here. Depending on the location of pain, there are also heat patches including Thermacare Back Heat Wrap, Deep Heat Patch Back Pain Patches, Cura-Heat Back Pain, Vitabiotics Jointace Patch, Bodytox Natural Warm Patches, Voltarol Heat Patches and Belladonna Large Plaster.

Infrared Sauna – Emits infrared energy which allows heat to deeply penetrate tissues to reduce pain (131). It has been shown to assist those with chronic pain (132). In terms of IBS, the theory is that the heat penetration causes a brief elevation in body temperature producing an artificial fever which boosts the immune system helping to fight infections (133). However, there does not seem to be studies specific to this treatment and IBS. There are some dangers to consider with this type of therapy.

Infrared Laser – is used by a product called coMra which claims to treat pain. In 2015, the British Advertising Authority (ASA) ordered companies to stop claiming that devices such as coMra help solve health problems (167). An article in the British Medical Journal (BMJ) also stated that coMra therapy is “non-evidence based medicine” (168).

Deep Tissue Laser Therapy – for the general treatment of neuropathic pain, but not as yet mentioned in relation to IBS pain. Studies have shown it beneficial in patients with peripheral neuropathic pain in older adults with type 2 diabetes (151). Further research is needed (152) in particular in regards to IBS and some studies show mixed results regarding neuropathic pain (153).

Acupuncture – acupuncture has shown mixed results for the treatment of IBS pain. Some people find that it helps them, other people do not benefit from it. (43) A clinical trial of acupuncture for IBS-D patients at a rate of 3 times per week, total 36 sessions during a period of 12 weeks has been discussed (52). An overview of acupuncture is contained here: (53). This also includes a link to the accredited register of acupuncture practitioners in the UK. The cost may be prohibitive for the number of sessions that may be required e.g. for initial consultation of £60 and £40/hour each session, extrapolating that to the 36 session trial, this would be a cost of £1,500 for something that may or may not work. Meta-analysis suggests that the benefit of acupuncture on IBS symptoms is no better than placebo (118).

Acupuncture-moxibustion – a technique in which the herb mugwort is burned over specific acupuncture points; it is believed that its effects reach deeper into the body (110). Clinical trials have shown acupuncture-moxibustion helps to improve low threshold of the rectal sensation, gut motility, and pain perception (70) (111). When compared to electroacupuncture, acupuncture-moxibustion was superior in terms of improving diarrhoea in IBS particularly those who react to cold drink/food. (112)

Electroacupuncture – uses acupuncture needles to deliver an electrical current to acupuncture points. In addition to helping with visceral pain, it has also been shown to help motility in IBS-C patients. Its treatment of constipation was superior to acupuncture-moxibustion. (112)

TENS – Transcutaneous electrical nerve stimulation (TENS) is a method of pain relief involving the use of a mild electrical current (45). In a study TENS was found to slightly reduce chronic pelvic and/or abdominal pain (47). Transcranial direct current stimulation (tDCS), is a non-invasive, painless brain stimulation treatment that uses direct electrical currents to stimulate specific parts of the brain (46). In the same study it was found that combining TENS and tDCS in patients suffering from chronic pelvic and/or abdominal pain produced no additional benefit, compared to TENS alone (47). 

With standard TENS, pain relief is experienced quickly, but can wear off soon after TENS treatment is stopped. The pain relief from lower frequency TENS is slower acting but stimulates the pain control effects of the endogenous opioid system for a long period, anywhere between 5 minutes and 18 hours. Some don’t return to pre-TENS pain levels until 24 hours after treatment. The length of pain relief varies from person to person. It is possible the extent of endogenous opioids a person has might impact the amount and duration of pain relief. Due to individual responses, this means there is no standard recommendation for the length of TENS treatment, with advice varying between 20 minutes to several hours. Studies found that TENS may change neuronal pathways, since it provide cumulative pain relieving effects after multiple applications. However, the body might get used to TENS treatment, making it less effective. Having breaks between treatment and/or changing electrode positions or electrical settings might help guard against this. (50)

TEAS – Transcutaneous electrical acustimulation applies mild electrical current via self-adhesive electrodes to acupuncture points. Conversely, TENS doesn’t use acupuncture points. A study found that twice per week for 4 weeks of TEAS treatment improved abdominal pain/discomfort significantly (48). However, a Google search did not find any practitioners using this technique apart from a clinical trial to investigate TEAS for patients with IBS-C and pain (49).

FSM – Frequency Specific Microcurrent is similar to TENS but delivers a much lower current level and specific frequencies to target specific problems. It is mentioned in relation to IBS, but there doesn’t seem to be specific studies regarding IBS.

TMS – Transcranial magnetic stimulation uses magnetic fields to stimulate nerve cells in the brain. It has been approved by the FDA to treat major depression (when other options have been tried), OCD, migraines and a last resort for smoking cessation (190). It’s application for functional bowel disorders such as IBS has not been well studied, though it has been used for pain relief in China and a few researchers in China have used the treatment for functional bowel disorders with promising results (191). However, rTMS (Repetitive Transcranial Magnetic Stimulation) has elicited some life changing outcomes for fibromyalgia sufferers in UK (192).

Scrambler Therapy – Approved by the FDA for the treatment of peripheral neuropathy, it involves two electrode pads emitting low electrical voltage, one placed inches from the site of pain and the other on the part of the body not affected by pain. This helps to scramble the nerve impulses to the brain such that a ‘no pain’ signal replaces a pain signal. (154). It was used in a study in the treatment of chronic chemotherapy-induced peripheral neuropathy (155). There is a discussion on Healthunlocked about this therapy here.

Percutaneous electrical nerve field stimulator (PENFS) – The prescription only percutaneous electrical nerve field stimulator device called IB-Stim has been approved by the FDA to help reduce IBS related abdominal pain in adolescents aged 11 to 18. It is placed behind the patient’s ear and works by sending gentle electrical impulses into cranial nerve bundles located in the ear which stimulates parts of the brain involved in pain processing. 27 patients ages 11 to 18 used the device for three weeks. Pain was reduced by 30% in 52% of that group, compared to 30% of the 23 patients who received a placebo. (150)

Transcutaneous auricular vagal nerve stimulation (taVNS) – appears to be the same/similar mechanism to PENFS. It stimulates the vagus nerve via by sending electrical impulses to vagus nerve connections in the outer ear. (171) In a study, it improved both constipation and abdominal pain in IBS-C patients (172) and appears to be safe (173). Stimulating the vagus nerve switches on the body’s parasympathetic nervous system, or “rest and digest” system. Further information here, here and here. IBS patient discussion on this here and here.

Pulsed electromagnetic field (PEMF) Therapy – helps pain management by for example, improving circulation of oxygen and nutrients to cells and reducing inflammation (142). It is mentioned related to chronic pain conditions such as fibromyalgia, but a study found no difference between PEMF and placebo (143). However, an electromagnetic pulse therapy device called AciPatch seems to have good reviews on Amazon in relation to pain relief.

Topical Applications – may help specifically located neuropathic pain, but are not particularly mentioned in relation to IBS. These include Arnica (further information here), Frankincense & Myrrh (further information here), Topricin and capsaicin. Capsaicin comes from chilli peppers and it what makes chilli peppers hot. It can help block pain messages to nerves. It mainly comes in the form of creams and patches. Capsaicin patches, such as Qutenza (reviews here), have a higher concentration of capsaicin, relief can last up to 3 months, but they need to be administered by a doctor. There can be side effects such as burning and itching (135), making skin more sensitive to the sun and heat. There can be rare heart related side effects such as slow or fast pulse rate and high blood pressure (134) (136) (137) (139). Capsaicin’s pain relief is related to its impact on TRPV1 channels (138) (140). Topical mint oil works by its cooling mechanism activating TRPM8 receptors in skin, which subsequently inhibit pain messages being sent from the local area where pain is experienced to the brain (166). Commercial products using mint oil to take advantage of this mechanism are BeYou Patches and Natural Patches of Vermont. There is anecdotal evidence of Tiger Balm helping with abdominal pain here.

Oral Capsaicin (141) – in addition to topical capsaicin mentioned above, a study found that 600 mg/daily enteric-coated capsules of red pepper for 6 weeks significantly decreased the intensity of abdominal pain and bloating and improved visceral sensitivity in IBS sufferers (141a).

There is a product called Super Nerve Power which claims to treat pain. However, please note that when I originally clicked on the related company’s link, Malwarebytes identified the company’s website as malvertising. I’ve noticed that the company’s website now no longer works and they have a shop on Amazon instead. Their shop says that the product is ‘clinically proven’, but I can’t find any related studies and they do not substantiate their claims.

Further Reading And References

(1) IFFGD: Understanding and Managing Pain in Irritable Bowel Syndrome (IBS), aboutibs.org, International Foundation for Gastrointestinal Disorders

(2) IFFGD: Common Questions About Functional Abdominal Pain Syndrome (FAPS), International Foundation for Gastrointestinal Disorders

(3) IFFGD: Centrally Mediated Abdominal Pain Syndrome, International Foundation for Gastrointestinal Disorders

(4) Niamh Michail: EFSA raises red flag for silicon dioxide safety over nanoparticles, 18-Jan-2018

(5) Kathleen M., Edited by Moderator: Morning abdominal pain, IBSgroup.org, Jan 26, 2009

(6) University of California – Los Angeles, additional authors include M. Catherine Bushnell, Ph.D., of McGill University, and Jennifer B. Labus, Joshua A. Bueller, Kirsten Tillisch and Bruce D. Naliboff, Ph.D., all of UCLA: Structural brain alterations in patients with irritable bowel syndrome discovered, July 23, 2010

(7) Dr. I. Farahat: Typical & Atypical IBS Pain Locations (Diagram Included), oh-mygut.com, Last Updated: July 27, 2023

(8) Zawn Villines, Medically reviewed by Cynthia Taylor Chavoustie, MPAS, PA-C: What causes back pain and gas, medicalnewstoday.com,  Updated on January 11, 2024

(9) Christopher Duncan, DC, CCSP, LMT, Answer requested by Sudip Gautam: How can gas be related to lower back pain?, quora.com

(10) IBS Network: HOW CAN I MANAGE THE PAIN?, theibsnetwork.org

(11) Ann Pietrangelo, Medically reviewed by George Krucik, MD, MBA: IBS and Back Pain, healthline.com, Updated on May 31, 2023

(12) Jennifer Smith: IBS Pain Guide: Types, Locations, and Treatments, mindsethealth.com, November 25, 2020

(13) Jennifer Couzin-Frankel: What causes irritable bowel syndrome pain? It may be a local immune reaction, sciencemag.org, Jan. 13, 2021

(14) IBS Patient Support Group: IBS Medications, Last updated on Sep 19, 2023

(15) Törnblom H, Drossman DA. Psychotropics, Antidepressants, and Visceral Analgesics in Functional Gastrointestinal Disorders. Curr Gastroenterol Rep. 2018 Nov 5;20(12):58. doi: 10.1007/s11894-018-0664-3. PMID: 30397821; PMCID: PMC6223713. – Table 1.

(16) Törnblom H, Drossman DA. Psychotropics, Antidepressants, and Visceral Analgesics in Functional Gastrointestinal Disorders. Curr Gastroenterol Rep. 2018 Nov 5;20(12):58. doi: 10.1007/s11894-018-0664-3. PMID: 30397821; PMCID: PMC6223713.

(17)  Kat Gál, Medically reviewed by Jennie Olopaade, PharmD, RPH: Anticholinergic drugs: What to know, medicalnewstoday.com, Updated on June 10, 2024

(18) Wikipedia, Agonist, Last edited on 7 July 2024

(19) Wikipedia, κ-opioid receptor, Last edited on 30 July 2024

(20) GI Society, Canadian Society of Intestinal Research: Irritable Bowel Syndrome (IBS) and Serotonin, badgut.org, First published in the Inside Tract® newsletter issue 144 – July/August 2004

(21) Angèle P. M. Kerckhoffs, José J. M. ter Linde, Louis M. A. Akkermans, and Melvin Samsom1: SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome
patients regardless of visceral sensitivity state in large intestine, Am J Physiol Gastrointest Liver Physiol 302: G1053–G1060, 2012. First published February 9, 2011; doi:10.1152/ajpgi.00153.2011.

(22) Alexander J. German, Jill E. Maddison, Grant Guilford, Chapter 19 – Gastrointestinal drugs, Editor(s): JILL E MADDISON, STEPHEN W PAGE, DAVID B CHURCH, Small Animal Clinical Pharmacology (Second Edition), W.B. Saunders, 2008, Pages 469-497,
ISBN 9780702028588, https://doi.org/10.1016/B978-070202858-8.50021-X.
(https://www.sciencedirect.com/science/article/pii/B978070202858850021X)

(23) Barbara Bolen, PhD, Medically reviewed by Sonal Kumar, MD, MD: Can Antispasmodics Treat IBS?, verywellhealth.com, Updated on April 28, 2023

(24) Pharmacy Author: Omudhome Ogbru, PharmDMedical and Pharmacy Editor: Jay W. Marks, MD: Anticholinergic and Antispasmodic Drugs, medicinenet.com, Medically Reviewed on 11/7/2022

(25) NHS: How and when to take mebeverine, Page last reviewed: 17 February 2023

(26) NHS: Buscopan (hyoscine butylbromide), Page last reviewed: 14 October 2021

(27) Medically reviewed by Drugs.com: Linaclotide Side Effects, Last updated on Jul 1, 2024.

(28) Medicine.net: What are the side effects of Trulance?

(29) NHS: Side effects of Loperamide, Page last reviewed: 10 April 2024

(30) Medically reviewed by Drugs.com: Eluxadoline Dosage, Last updated on June 23, 2020.

(31) University of Illinois and Carly Vandergriendt, Medically reviewed by Jennie Olopaade, PharmD, RPH: Imodium Usage, Dosage, and Side Effects, Updated on April 17, 2023

(32) Medically reviewed by Drugs.com: Prucalopride Side Effects, Last updated on Jun 26, 2024

(33) Divya Jacob, Pharm. D,  Medical and Pharmacy Editor: Sarfaroj Khan, BHMS, PGD Health Operations: HOW DO SELECTIVE 5-HT3 RECEPTOR ANTAGONISTS WORK?, RxList

(34) Fukudo S, Matsueda K, Haruma K, Ida M, Hayase H, Akiho H, Nakashima Y, Hongo M. Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: A randomized, placebo-controlled phase II study. Neurogastroenterol Motil. 2017 Jun;29(6). doi: 10.1111/nmo.13023. Epub 2017 Feb 16. PMID: 28205278.

(35) NHS: Pregabalin, Page last reviewed: 16 November 2021

(36) Dmitriy Kedrin, MD, PhD: Pregabalin effective for treating pain, bloating, diarrhea in IBS, Healio Gastroenterology, January 21, 2019

(37) Thiwan SI, Drossman DA. Treatment of Functional GI Disorders With Psychotropic Medicines: A Review of Evidence With a Practical Approach. Gastroenterol Hepatol (N Y). 2006 Sep;2(9):678-688. PMID: 28316538; PMCID: PMC5350580.

(38) Poong-Lyul Rhee, Prof., Samsung Medical Center: Colonoscopy-related Pain Predicts the Treatment Response of Amitriptyline in Patients With Irritable Bowel Syndrome, clinicaltrials.gov, December 24, 2015

(39) US Pharmacist: Nearly All Antidepressants for Chronic Pain Present Side-Effect Issues, SEPTEMBER 20, 2017

(40) Principal Investigator: Gregory S. Sayuk, MD, Washington University School of Medicine: Irritable Bowel Syndrome (IBS) Functional Magnetic Resonance Imaging (fMRI) With Desipramine, clinicaltrials.gov, First Posted: April 14, 2009, Last Update Posted: August 31, 2022

(41) R. SPILLER: Review article: probiotics and prebiotics in irritable bowel syndrome, Wolfson Digestive Diseases Centre, University Hospital, University of Nottingham, First published: 23 July 2008 https://doi.org/10.1111/j.1365-2036.2008.03750.x

(42) Steven Graefe; Shamim S. Mohiuddin.: Biochemistry, Substance P, Last Update: July 30, 2023.

(43)  Adam Rowden, Medically reviewed by Kerry Boyle D.Ac., M.S., L.Ac., Dipl. Ac., CYT: Can acupuncture treat irritable bowel syndrome?, MedicalNewsToday, January 28, 2022

(44) HealthDay News: St. John’s Wort Doesn’t Ease Irritable Bowel Syndrome, news24.com, 08 Jan 2010

(45) NHS: TENS (transcutaneous electrical nerve stimulation), Page last reviewed: 13 April 2022

(46) John Hopkins Medicine: Transcranial Direct Current Stimulation (tDCS)

(47) Harvey MP, Watier A, Dufort Rouleau É, Léonard G. Non-invasive stimulation techniques to relieve abdominal/pelvic pain: Is more always better? World J Gastroenterol. 2017 May 28;23(20):3758-3760. doi: 10.3748/wjg.v23.i20.3758. PMID: 28611529; PMCID: PMC5449433.

(48) Shuping Chen, Shubin Wang, Peijing Rong, Junying Wang, Lina Qiao, Xiumei Feng, Junling Liu, Jianliang Zhang, “Acupuncture for Visceral Pain: Neural Substrates and Potential Mechanisms”, Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 609594, 12 pages, 2014. https://doi.org/10.1155/2014/609594

(49) Jiande Chen, Ph.D.: Optimization of Transcutaneous Electrical Acustimulation Modalities for Treatment of IBS-C (TEA), University of Michigan, clinicaltrials.gov, First Submitted: 28 June, 2021 

(50) Nursing Times: Exploring the evidence for using TENS to relieve pain, 09 MARCH, 2012

(51) Alok Jha: Heat ‘relieves internal pain’, UCL News, 5 July 2006

(52) Pei L, Chen H, Guo J, Chen L, Wu X, Xu W, Weng S, Yang E, Hammer T, Sun J. Effect of acupuncture and its influence on visceral hypersensitivity in IBS-D patients: Study protocol for a randomized controlled trial. Medicine (Baltimore). 2018 May;97(21):e10877. doi: 10.1097/MD.0000000000010877. PMID: 29794793; PMCID: PMC6392752.

(53) NHS: Acupuncture, Page last reviewed: 28 February 2023

(54) Trinkley K.E., Nahata M.C.: Medication Management of Irritable Bowel Syndrome, 2014;89:253-267, https://doi.org/10.1159/000362405

(55) Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP: Appropriate Gabapentin Dosing for Neuropathic Pain, Pharmacy Times, December 20, 2017

(56) david96583: Gabapentin withdrawal after short term use?, patient.info forum

(57) Written by:Editorial StaffReviewed by:Dan Wagener: What Is the Withdrawal Timeline for Gabapentin?, Desert Hope Treatment Center, Updated: Feb 17, 2023

(58) NicoleB34: new stomach pain, not sure what to do, tmswiki.org, Apr 16, 2018

(59) David F. McAuley, Pharm.D. GlobalRPh Inc.: PREGABALIN VERSUS GABAPENTIN, GlobalRPh, The Clinician’s Ultimate Reference

(60) Drugs.com, Lyrica User Reviews & Ratings

(61) Drugs.com, User Reviews for Pregabalin to treat Neuropathic Pain

(62) Rey E, Mearin F, Alcedo J, Ciriza C, Delgado-Aros S, Freitas T, Mascarenhas M, Mínguez M, Santos J, Serra J. Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report. Adv Ther. 2017 Mar;34(3):587-598. doi: 10.1007/s12325-016-0473-8. Epub 2017 Jan 12. PMID: 28083815; PMCID: PMC5350198.

(63) Islam BN, Sharman SK, Browning DD. Clinical utility of plecanatide in the treatment of chronic idiopathic constipation. Int J Gen Med. 2018 Aug 10;11:323-330. doi: 10.2147/IJGM.S125051. PMID: 30127634; PMCID: PMC6089121.

(64) Shanti Eswaran, Amanda Guentner, and William D Chey: Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation, University of Michigan Health System, J Neurogastroenterol Motil 2014; 20(2): 141-151  https://doi.org/10.5056/jnm.2014.20.2.141

(65) Nottingham Area Prescribing Committee: Linaclotide, Dec 2021

(66) Christine B. Dalton, PA-C Douglas A. Drossman, MD: The Use of Antidepressants in the Treatment of Irritable Bowel Syndrome and Other Functional GI Disorders, UNC Center for Functional GI & Motility Disorders

(67) Chen L, Ilham SJ, Feng B. Pharmacological Approach for Managing Pain in Irritable Bowel Syndrome: A Review Article. Anesth Pain Med. 2017 Jan 25;7(2):e42747. doi: 10.5812/aapm.42747. PMID: 28824858; PMCID: PMC5556397.

(68) A. D. Sperber, D. A. Drossman: Review article: the functional abdominal pain syndrome, AP&T, First published: 04 January 2011 https://doi.org/10.1111/j.1365-2036.2010.04561.x

(69) NHS: Antihistamines, Page last reviewed: 16 May 2023

(70) Farzaei MH, Bahramsoltani R, Abdollahi M, Rahimi R. The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments. J Neurogastroenterol Motil. 2016 Oct 30;22(4):558-574. doi: 10.5056/jnm16001. PMID: 27431236; PMCID: PMC5056566.

(71) Barshop K, Staller K. New Pathways, New Targets: Visceral Hypersensitivity Pathogenesis in Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2016 Feb 25;7(2):e146. doi: 10.1038/ctg.2016.12. PMID: 26913769; PMCID: PMC4817414.

(72) KU Leuven: Hay fever medicine reduces symptoms of irritable bowel syndrome, sciencedaily.com, January 14, 2016

(73) Wikipedia, Ebastine, Page last edited on 15 July 2024

(74) DRUGBANK Online: Ketotifen

(75) Michael Stewart, MRPharmS, Peer reviewed by Sid Dajani: Ketotifen, patient.info, 24 Apr 2023 | Latest version

(76) Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21. doi: 10.1136/gut.2010.213108. Epub 2010 Jul 21. PMID: 20650926.

(77) Stanisor OI, van Diest SA, Yu Z, Welting O, Bekkali N, Shi J, de Jonge WJ, Boeckxstaens GE, van den Wijngaard RM. Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine-1-receptor antagonists. PLoS One. 2013 Jun 12;8(6):e66884. doi: 10.1371/journal.pone.0066884. PMID: 23776699; PMCID: PMC3680390.

(78) NHS: Fexofenadine, Page last reviewed: 14 October 2021

(79) Roberts DJ, Gispert J. The non-cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy. 1999 Jul;29 Suppl 3:151-5. doi: 10.1046/j.1365-2222.1999.0290s3151.x. PMID: 10444230.

(80) LISA RYAN, Could the misery of IBS be eased with hayfever tablets? Antihistamines ‘significantly reduce painful abdominal cramps’, dailymail.co.uk, PUBLISHED: 19:01, 14 January 2016 | UPDATED: 22:10, 14 January 2016

(81) Camilleri M, Ford AC. Pharmacotherapy for Irritable Bowel Syndrome. J Clin Med. 2017 Oct 27;6(11):101. doi: 10.3390/jcm6110101. PMID: 29077050; PMCID: PMC5704118.

(82) NICE: Irritable bowel syndrome in adults: diagnosis and management, Published: 23 February 2008 Last updated: 04 April 2017

(83) Medically reviewed by Drugs.com: Is Zelnorm back on the market?, Last updated on March 25, 2024.

(84) Bracco A, Jonsson B, Ricci J F, Drummond M, Nyhlin H. Economic evaluation of tegaserod vs placebo in the treatment of patients with irritable bowel syndrome: an analysis of the TENOR study. Value in Health 2007; 10(4): 238-246

(85) Wikipedia, Fedotozine

(86) Qutenza.com: HIGHLIGHTS OF PRESCRIBING INFORMATION

(87) Medically reviewed by Judith Stewart, BPharm: Qutenza, Drugs.com, Last updated on Aug 22, 2023

(88) Health Products Regulatory Authority [Ireland]: Introduction to QUTENZA™ – the capsaicin 8% patch

(89) NHS: Mesalazine, Page last reviewed: 19 July 2021

(90) Zhang C, Rui YY, Zhou YY, Ju Z, Zhang HH, Hu CY, Xiao Y, Xu GY. Adrenergic β2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats. PLoS One. 2014 Apr 14;9(4):e94726. doi: 10.1371/journal.pone.0094726. PMID: 24733123; PMCID: PMC3986230.

(91) NHS: Beta blockers, Page last reviewed: 02 December 2022

(95) Camilleri M, Ford AC. Pharmacotherapy for Irritable Bowel Syndrome. J Clin Med. 2017 Oct 27;6(11):101. doi: 10.3390/jcm6110101. PMID: 29077050; PMCID: PMC5704118.

(96) Menarini Group: 52-Week Efficacy and Safety Study of Ibodutant in Women With Irritable Bowel Syndrome With Diarrhea (IBS-D) (IRIS-4), ClinicalTrials.gov, First Posted: April 22, 2014, Last Update Posted: March 3, 2017

(97) Todd W Rice, Arthur P Wheeler, Gordon R Bernard: A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis, August 2010, Critical Care Medicine 38(8):1685-94, DOI:10.1097/CCM.0b013e3181e7c5c9, Source PubMed

(98) The influence of antibiotics and dietary components on gut microbiota Ruth K. Dudek-Wicher, Adam Junka, Marzenna Bartoszewicz Prz Gastroenterol. 2018; 13(2): 85–92. Published online 2018 May 25. doi: 10.5114/pg.2018.76005

(99) Elaine Watson: Academic rejects ‘fuzzy math’ claim in spat over curcumin bioavailability, NutraIngredients USA, 29-Apr-2011

(100) Akshat Rathi, Forget what you’ve heard: Turmeric seems to have zero medicinal properties, Quartz India, January 12, 2017

(101) Tang QL, Lai ML, Zhong YF, Wang AM, Su JK, Zhang MQ. Antinociceptive effect of berberine on visceral hypersensitivity in rats. World J Gastroenterol. 2013 Jul 28;19(28):4582-9. doi: 10.3748/wjg.v19.i28.4582. PMID: 23901236; PMCID: PMC3725385.

(102) Yu ZC, Cen YX, Wu BH, Wei C, Xiong F, Li DF, Liu TT, Luo MH, Guo LL, Li YX, Wang LS, Wang JY, Yao J. Berberine prevents stress-induced gut inflammation and visceral hypersensitivity and reduces intestinal motility in rats. World J Gastroenterol. 2019 Aug 7;25(29):3956-3971. doi: 10.3748/wjg.v25.i29.3956. PMID: 31413530; PMCID: PMC6689801.

(103) Heraldo A.C. Rocha, Thiago V. Rocha, Fernando J.F. Nóbrega, Liana C.S. Morais, Margareth F.F.M. Diniz, Randomized controlled trial of Panax ginseng in patients with irritable bowel syndrome, Revista Brasileira de Farmacognosia, Volume 28, Issue 2,
2018, Pages 218-222, ISSN 0102-695X, https://doi.org/10.1016/j.bjp.2018.02.007.

(104) Joseph Nordqvist, Medically reviewed by Debra Rose Wilson, Ph.D., MSN, R.N., IBCLC, AHN-BC, CHT: What are the health benefits of ginseng? – Side Effects, Updated on December 15, 2023

(105) WebMD: How to use Korean Ginseng – Side Effects

(106)  R. Morgan Griffin, Julie Marks, Medically Reviewed by Zilpah Sheikh, MD: Ginseng, WebMD, Reviewed October 31, 2023

(107) WebMD: Panax Ginseng

(108) Zhaoxiang Bian, ph.D: Efficacy and Safety of Chinese Medicine JCM-16021 for Diarrhea-predominant Irritable Bowel Syndrome, Chinese University of Hong Kong, ClinicalTrials.gov, First Posted  : March 7, 2018Last Update Posted  : August 19, 2020

(109) Croucher Foundation: Herbs for the gut: new drug for irritable bowel syndrome, 22 March 2019

(110) Ancient Wisdom Wellness Centre: Using acupuncture to treat irritable bowel syndrome (IBS), acupuncture123.co.uk

(111) Anastasi JK, McMahon DJ, Kim GH. Symptom management for irritable bowel syndrome: a pilot randomized controlled trial of acupuncture/moxibustion. Gastroenterol Nurs. 2009 Jul-Aug;32(4):243-55. doi: 10.1097/SGA.0b013e3181b2c920. PMID: 19696601.

(112) Shi Y, Chen YH, Yin XJ, Wang AQ, Chen XK, Lu JH, Ji R, Bao CH, Sun J, Zhao JM, Wu HG. Electroacupuncture versus Moxibustion for Irritable Bowel Syndrome: A Randomized, Parallel-Controlled Trial. Evid Based Complement Alternat Med. 2015;2015:361786. doi: 10.1155/2015/361786. Epub 2015 Jul 30. PMID: 26294923; PMCID: PMC4534607.

(113) Drugbank online: Pinaverium

(114) IBS Tales: Dicetel

(115): K. Avendaño, A. Calleri, N. González: Severe esophagitis due to pinaverium bromide, Revista Gastroenterologia Mexico, Vol. 83. Issue 4, October – December 2018, DOI: 10.1016/j.rgmxen.2018.06.001

(116) Dr Jane Varney, Dr CK Yao & Lyndal Collins – Research Dietitians: Probiotics for IBS, Monash University FODMAP Blog, 29 July 2021

(117) Darrell Hulisz, RPh, PharmD: Chronic Pain Management. Role of Newer Antidepressants and Anticonvulsants. US Pharmacist, MAY 18, 2007

(118) Lacy BE, Weiser K, De Lee R. The treatment of irritable bowel syndrome. Therap Adv Gastroenterol. 2009 Jul;2(4):221-38. doi: 10.1177/1756283X09104794. PMID: 21180545; PMCID: PMC3002524.

(119) Sansone RA, Sansone LA. Pain, pain, go away: antidepressants and pain management. Psychiatry (Edgmont). 2008 Dec;5(12):16-9. PMID: 19724772; PMCID: PMC2729622.

(120) – Dr. Megan Riehl, GI Health Psychologist, Behavioral Health Program, Antidepressants for the treatment of Functional Gastrointestinal Disorders, Michigan Medicine Division of Gastroenterology, Document adapted from literature available from the UNC Center for Functional GI & Motility Disorders

(121) NHS Lothian – Management of Pain and Bloating in Irritable Bowel Syndrome

(122) Obata H. Analgesic Mechanisms of Antidepressants for Neuropathic Pain. Int J Mol Sci. 2017 Nov 21;18(11):2483. doi: 10.3390/ijms18112483. PMID: 29160850; PMCID: PMC5713449.

(123) Jayne Leonard, Medically reviewed by Philip Ngo, PharmD: Gabapentin: What to know, Medical News Today, Updated on February 5, 2024

(124) Editorial Staff: What are the Long-Term Effects of Gabapentin?, Desert Hope Treatment Center, Updated: Oct 06, 2022

(125) Ericka Huckle, PharmD Candidate, Lauren McKnight, PharmD, CPP, BCACP: Neuropathic Pain, Pharmacy Times, Health-System Edition, March 2016, Volume 5, Issue 2, March 24, 2016

(126) Help for IBS: IBS Treatments & Diagnosis – Gut Directed Hypnotherapy

(127) Help for IBS: IBS Treatments & Diagnosis – IBS Terms & Definitions – Brain Gut Dysfunction & IBS

(128) Song GH, Leng PH, Gwee KA, Moochhala SM, Ho KY. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut. 2005 Oct;54(10):1402-7. doi: 10.1136/gut.2004.062034. Epub 2005 May 24. PMID: 15914575; PMCID: PMC1774717.

(129) Li, Qian MS, PhD¹; King, Andrew J. PhD²; Liu, Liansheng MD¹; Zhu, Yaohui MD¹; Caldwell, Jeremy S. PhD²; Pasricha, Pankaj J. MD¹. Tenapanor Reduces IBS Pain Through Inhibition of TRPV1-Dependent Neuronal HyperexcitabilityIn vivo: 484. American Journal of Gastroenterology 112():p S255, October 2017.

(130) Tenapanor for Irritable Bowel Syndrome with Constipation, NIHR Innovation Observatory Evidence Briefing: February 2018

(131) Chelsea Clark: 8 Natural Pain Killers That May Provide Natural Pain Relief, University Health News, April 9, 2020

(132) Conscious Spaces – the science of wellbeing: Infrared saunas: the health truths behind celebrity hype, November 20, 2019

(133)  Caitlin Stores: Can an infrared sauna boost your immune system?, ENDEAVOUR College of Natural Health, 6 August 2020

(134) Colleen de Bellefonds, Medically Reviewed by Sanjay Ponkshe: What Is Capsaicin?, WebMD, June 03, 2023

(135) NHS: Treatment – Peripheral neuropathy, Page last reviewed: 10 October 2022

(136) Baranidharan G, Das S, Bhaskar A. A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain. Ther Adv Neurol Disord. 2013 Sep;6(5):287-97. doi: 10.1177/1756285613496862. PMID: 23997814; PMCID: PMC3755533.

(137) Victor Fattori , Miriam S. N. Hohmann, Ana C. Rossaneis, Felipe A. Pinho-Ribeiro and Waldiceu A. Verri Jr.: Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses, MDPI – molecules review

(138) Magdalene M Moran, Arpad Szallasi: Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field, British Journal of Pharmacology, 19 September 2017 https://doi.org/10.1111/bph.14044

(139) Chung MK, Campbell JN. Use of Capsaicin to Treat Pain: Mechanistic and Therapeutic Considerations. Pharmaceuticals (Basel, Switzerland). 2016 Nov;9(4). DOI: 10.3390/ph9040066. PMID: 27809268; PMCID: PMC5198041.

(140) Drugbank Online: Capsicum oleoresin

(141) O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev. 2012 Oct;64(4):939-71. doi: 10.1124/pr.112.006163. PMID: 23023032; PMCID: PMC3462993.

(141a) Stefano Evangelista (2015) Novel therapeutics in the field of capsaicin and pain, Expert Review of Clinical Pharmacology, 8:4, 373-375, DOI: 10.1586/17512433.2015.1044438

(142) Medical Device News Magazine: Could PEMF Therapy Help With Chronic Pain?, May 20, 2021

(143) Multanen, Juhani & Häkkinen, Arja & Heikkinen, Pauli & Kautiainen, Hannu & Mustalampi, Sirpa & Ylinen, Jari. (2017). Pulsed electromagnetic field therapy in the treatment of pain and other symptoms in fibromyalgia: A randomized controlled study. Bioelectromagnetics. 39. 10.1002/bem.22127.

(144) Rene van den Wijngaard: Does functional abdominal pain have an organic explanation? Gut-localized immune responses offer new clues for patients with functional gastrointestinal disorders, Gut Microbiota for Health, March 8th, 2021

(145) Stephani Sutherland: How Food Triggers the Pain of Irritable Bowel Syndrome, PAINRESEARCHFORUM, 17 Mar 2021

(146) Dr. Liji Thomas, MD, reviewed by Dr. Jennifer Logan, MD, MPH: Long Term Effects of Taking Allergy Medications, News Medical, Last Updated: Sep 11, 2019

(147) Dr. Sanchari Sinha Dutta, Ph.D., reviewed by Dr. Jennifer Logan, MD, MPH: Fibromyalgia and Gut Health: SIBO and IBS, New Medical, Last Updated: Jun 10, 2019

(148) MaryAnn De Pietro, CRT, Medically reviewed by Jenneh Rishe, RN: Bowel endometriosis: What to know, Medical News Today, Updated on May 26, 2023

(149) John P. Cunha, DO, FACOEP, Medical Editor: Bhupinder S. Anand, MBBS, MD, DPHIL (OXON): Peptic Ulcers, emedicinehealth, Reviewed on 8/17/2022

(150) Susan Kelly: Stimulation device for IBS pain in children gains De Novo clearance, MEDTECHDIVE,  June 10, 2019

(151) Chatterjee, P., Srivastava, A.K., Kumar, D.A. et al. Effect of deep tissue laser therapy treatment on peripheral neuropathic pain in older adults with type 2 diabetes: a pilot randomized clinical trial. BMC Geriatr 19, 218 (2019). https://doi.org/10.1186/s12877-019-1237-5

(152) Jeffrey R. Basford, M.D., Ph.D: Low-Energy Laser Treatment of Pain and Wounds: Hype, Hope, or Hokum?, Mayo Clinic Proceedings, EDITORIAL| VOLUME 61, ISSUE 8, P671-675, AUGUST 01, 1986, DOI:https://doi.org/10.1016/S0025-6196(12)62034-5

(153) Leah Alexander, MD, FAAP: Laser Treatment for Neuropathy – Is It Effective?, HealthPages.org, Last Updated On December 28, 2022

(154) Staff Sgt. Joe Yanik: Nerve Scrambler Therapy lessens pain for warfighters, TRICARE patients, Air Force Medical Service, Nov. 2, 2017

(155) Nick DeVito and Ben Goldacre: Unreported clinical trial of the week: Scrambler therapy in the treatment of chronic chemotherapy-induced peripheral neuropathy (NCT02111174), thebmjopinion, May 29, 2018

(156) Wikipedia: Opiorphin

(157) OLIVIA LERCHE: Painkiller breakthrough: Drug as strong as MORPHINE but without side-effects discovered, express.co.uk, Jan 16, 2017

(158) Moss LM, Berends CL, van Brummelen EMJ, Kamerling IMC, Klaassen ES, Bergmann K, Ville V, Juarez-Perez V, Benichou AC, Groeneveld GJ. First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management. Br J Clin Pharmacol. 2022 Jan;88(1):103-114. doi: 10.1111/bcp.14931. Epub 2021 Jul 16. PMID: 34046921; PMCID: PMC9292820.

(159) Monique Van Velzen: Dose Finding Study of STR-324, ClinicalTrials.gov, Last Update July 13, 2021

(160) King’s College London, News Centre: Pioneering pain research leads to landmark deal, 8 March 2019

(161) Genetic Engineering & Biotechnology News: Merck, King’s Launch $344M+ Chronic Pain Drug Collaboration, March 11, 2019

(162) Stony Brook University News: New Painkiller with No Apparent Side Effects or Addictive Qualities Near to Market, January 25, 2011

(163) Stephani Sutherland: Pain Therapies, BrainFacts/SfN, 25 Oct 2016

(164) ENDPOINTS: Nav1.7 analgesic failures stack up as Biogen abandons vixotrigine after latest setback, October 24, 2018

(165) King’s College London: Scientists reveal new avenue for drug treatment in neuropathic pain, Medical Xpress, NOVEMBER 24, 2017

(166) University of Edinburgh. “‘Mint’ Pain Killer Takes Leaf Out Of Ancient Medical Texts.” ScienceDaily. ScienceDaily, 22 August 2006. <www.sciencedaily.com/releases/2006/08/060821220001.htm>.

(167) Stephen Barrett, M.D.: Regulatory Actions Related to EAV Devices, Quackwatch, March 4, 2022

(168) Margaret McCartney: What a new consumer health magazine doesn’t tell you, BMJ | 13 OCTOBER 2012 | VOLUME 345

(169) Madhusudhan R. Sanaka, D.Roy Ferguson, Annette Kyprianou, Hemangi Kale, Kevin D. Mullen, Saeid Amini: Does Instillation of Peppermint Oil Solution in the Cecum Facilitate Terminal Ileal Intubation? A Prospective, Randomized, Double-blind Study, GIE Gastrointestinal Endoscopy, ABSTRACTS| VOLUME 59, ISSUE 5, PP265, APRIL 2004, DOI:https://doi.org/10.1016/S0016-5107(04)01176-9

(170) William Moore, Medically Reviewed by Arefa Cassoobhoy, MD, MPH: Peppermint Oil for IBS: Does it Work?, WebMD, Reviewed September 21, 2023

(171) Wang Y, Li SY, Wang D, Wu MZ, He JK, Zhang JL, Zhao B, Hou LW, Wang JY, Wang L, Wang YF, Zhang Y, Zhang ZX, Rong PJ. Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application. Neurosci Bull. 2021 Jun;37(6):853-862. doi: 10.1007/s12264-020-00619-y. Epub 2020 Dec 23. PMID: 33355897; PMCID: PMC8192665.

(172) Shi X, Hu Y, Zhang B, Li W, Chen JD, Liu F. Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation. JCI Insight. 2021 Jul 22;6(14):e150052. doi: 10.1172/jci.insight.150052. PMID: 34138761; PMCID: PMC8410029.

(173) Kim AY, Marduy A, de Melo PS, Gianlorenco AC, Kim CK, Choi H, Song JJ, Fregni F. Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Sci Rep. 2022 Dec 21;12(1):22055. doi: 10.1038/s41598-022-25864-1. PMID: 36543841; PMCID: PMC9772204.

(174) Chesterfield PCT Health Psychology Service: The gate control theory of pain, Sherwood Forest Hospitals NHS Foundation Trust, Leaflet code: PIL3075, Created: Feb 2012 / Review Date: Feb 2014

(175) PainHEALTH: Neuroplasticity, Government of Western Australia Department of Health, Last updated: 28 Oct 2023

(176) Hanna-Jairala, Ignacio MD¹; Drossman, Douglas A. MD, MACG². Central Neuromodulators in Irritable Bowel Syndrome: Why, How, and When. The American Journal of Gastroenterology 119(7):p 1272-1284, July 2024. | DOI: 10.14309/ajg.0000000000002800

(177) MedBroadcast: Dicetel (pinaverium bromide)

(178) Soubra M, Schey R. Lubiprostone for the treatment of adult women with irritable bowel syndrome with constipation. Clin Med Insights Gastroenterol. 2012 Apr 10;5:23-30. doi: 10.4137/CGast.S7625. PMID: 24833931; PMCID: PMC3987758.

(179) Herekar A, Shimoga D, Jehangir A, Shahsavari D, Yan Y, Karunaratne TB, Sharma A. Tenapanor in the Treatment of Irritable Bowel Syndrome with Constipation: Discovery, Efficacy, and Role in Management. Clin Exp Gastroenterol. 2023 Jun 7;16:79-85. doi: 10.2147/CEG.S384251. PMID: 37309470; PMCID: PMC10257918.

(180) Goodoory VC, Tuteja AK, Black CJ, Ford AC. Systematic Review and Meta-analysis: Efficacy of Mesalamine in Irritable Bowel Syndrome. Clin Gastroenterol Hepatol. 2024 Feb;22(2):243-251.e5. doi: 10.1016/j.cgh.2023.02.014. Epub 2023 Feb 27. PMID: 36858143.

(181) Tuteja AK, Leung DT, Fang JC, Talley NJ, Stoddard GJ. Randomized double-blind placebo-controlled study to evaluate the effect of long-acting mesalamine on postinfectious irritable bowel syndrome with diarrhea. Neurogastroenterology & Motility. 2024; 00:e14889. doi:10.1111/nmo.14889

(182) Elhaggar, Sahr & Hegazy, Sahar & Abd-elsalam, Sherief & Bahaa, Mostafa. (2021). Open‐label pilot study of ethosuximide as adjunctive therapy for relieving abdominal pain related to Irritable Bowel Syndrome. Journal of Clinical Pharmacy and Therapeutics. 47. 10.1111/jcpt.13556.

(183) Roger Dobson: Bacteria pill for IBS helps to fight the misery of bloating by soaking up ‘rotten egg gas’, Daily Mail, 22 April 2019

(184) Anubhav Das, Eamonn M. Quigley, Alex Stevenson, Ian B. Jeffery: EP172 IMPACTS OF THE ADMINISTRATION OF BLAUTIX®, A THERAPEUTICALLY ACTIVE STRAIN OF BLAUTIA HYDROGENOTROPHICA, ON GUT MICROBIOTA STRUCTURE IN IRRITABLE BOWEL SYNDROME (IBS), Gastroenterology aga, Volume 164, ISSUE 6, SUPPLEMENT , S-1226-S-1227, May 2023, DOI:https://doi.org/10.1016/S0016-5085(23)03848-9

(185) Zheng, Y., Ching, J., Cheng, C.W. et al. Efficacy and safety of Chinese medicine JCM-16021 for diarrhea-predominant irritable bowel syndrome: study protocol for a multi-center, randomized, double-blind, placebo controlled clinical trial. Chin Med 16, 117 (2021). https://doi.org/10.1186/s13020-021-00530-2

(186) Ionescu, V.A.; Gheorghe, G.; Georgescu, T.F.; Bacalbasa, N.; Gheorghe, F.; Diaconu, C.C. The Latest Data Concerning the Etiology and Pathogenesis of Irritable Bowel Syndrome. J. Clin. Med. 2024, 13, 5124. https://doi.org/10.3390/jcm13175124

(187) Gintautas Grabauskas, Xiaoyin Wu, Jun Gao, Ji-Yao Li, Danielle Kim Turgeon, Chung Owyang,
Prostaglandin E2, Produced by Mast Cells in Colon Tissues From Patients With Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice, Gastroenterology, Volume 158, Issue 8,
2020, Pages 2195-2207.e6, ISSN 0016-5085, https://doi.org/10.1053/j.gastro.2020.02.022.

(188) The Cleveland Clinic: Hypothalamic-Pituitary-Adrenal (HPA) Axis, Last reviewed on 04/12/2024.

(189) Andreu Prados: Why do gastrointestinal symptoms follow a meal? Clues are emerging, gutmircobiotaforhealth.com, October 14th, 2024

(190) Mayo Clinic Staff: Transcranial magnetic stimulation, Mayo Clinic

(191) Li G, Jin B, Fan Z. Clinical application of transcranial magnetic stimulation for functional bowel disease. Front Med (Lausanne). 2023 Jun 16;10:1213067. doi: 10.3389/fmed.2023.1213067. PMID: 37396913; PMCID: PMC10311555.

(192) Samantha Leathers: I tried a new treatment for fibromyalgia and it’s given me my life back, Surrey Live, 28 OCT 2024

(193) Mariana Brizuela, Joel Castro, Andrea M. Harrington, and Stuart M. Brierley: Pruritogenic mechanisms and gut sensation: putting the “irritant” into irritable bowel syndrome, American Journal of Physiology-Gastrointestinal and Liver Physiology 2021 320:6, G1131-G1141

(194) Technology Networks – Biopharma: How Giant Spider Venom Might Help Sufferers of Irritable Bowel Syndrome,  Published: September 22, 2020

(195) Cardoso FC, Castro J, Grundy L, Schober G, Garcia-Caraballo S, Zhao T, Herzig V, King GF, Brierley SM, Lewis RJ. A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome. Pain. 2021 Feb 1;162(2):569-581. doi: 10.1097/j.pain.0000000000002041. PMID: 32826759.