Capsaicin, Corticosteroids, and CCK Antagonists

CAPSAICIN (Zostrix)

Capsaicin is an alkaloid derived from the chilli pepper which has been known in Europe since the time of Columbus in the fifteenth century. 150 years ago, Turnbull([i]) recognised that tincture of capsicum was helpful in treating chilblains and toothache. Capsaicin is the active ingredient in peppers which causes the burning sensation when you eat them.

There is a specific receptor that is activated by capsaicin (termed vanilloid receptor subtype 1 orVR1)which is implicated in both the treatment of chronic pain and urinary incontinence.

Repeated applications deactivate the capsaicin receptor: overstimulating the receptor may destroy the sensory nerve endings.

Repeated administration of Capsaicin is known deplete peripheral neuropeptides, notably Substance P which is known to be essential in pain transmission and is involved in inflammatory conditions such as arthritis. It is therefore most useful for pain of peripheral origin, such as postherpetic neuralgia or diabetic neuropathy.

An easy way to picture this process is to think of what happens when you first eat spicy food: there is a lot of burning in the mouth. However, if you become accustomed to eating curries or chili, you are able to eat food that you would previously found caused intolerable burning.

It is important to note that after a single exposure to capsaicin, the burning occurs rapidly and wears off slowly. Repeated exposure before the burning has dissipated may lead to sensitisation: more intense pain. However, if the exposure is repeated after the burning has stopped, desensitisation occurs: reduction in pain. It seems that capsaicin raises the pain threshold and this can be further raised by gradually increasing the concentration in a series of repeated applications.

Recent literature on treatment of postherpetic neuralgia suggests that capsaicin is a useful part of the clinical armamentarium for this condition. It may also be helpful in orofacial pain, trigeminal neuralgia, atypical facial neuralgia and Burning Mouth Syndrome. Berger et al([ii]) described an extemporaneous formulation of cayenne pepper candy used to treat mouth pain secondary to chemotherapy or radiotherapy; they varied the amount of cayenne pepper, which allowed them to escalate the concentration as the patients’ tolerance developed. Patients who became desensitised to low concentrations tolerated exposure to higher concentrations more easily.

USING CAPSAICIN:

It is available in 0.025-0.075% strength cream/gel OTC. Generally speaking, an adequate trial of capsaicin requires 4 applications a day for 4 weeks. The burning sensation may be relieved by local anaesthetic gel (lidocaine 0.5%) McCleane ([iii]) has tried glyceryl trinitrate (GTN) added to the cream and found that this reduces the burning and may also enhance the analgesic effect.

"Capsaicin usually burns when first applied. It sometimes takes more than a day or two for the effect to kick in, which is when the burning sensation stops. So spending a little more time building up a tolerance to the burning sensation might be one way to make the discomfort a bit more bearable.... It takes something with true detergent action to get this stuff off your skin -- a mild baby shampoo or dish liquid is your best bet -- and a wipe-down with rubbing alcohol won't hurt either. But if you can tolerate it on your skin for at least 15 minutes (so say the package inserts) you will get the benefit even if you have to wash it off later." Source: Anonymous. ([iv])

Adverse effects: as mentioned: burning after each application for up to 5 days after first application.

CAPSAICIN IN COMBINATION:

McCleane has recently published (June 2000[v] ) results of a study of topical application of doxepin hydrochloride, capsaicin and a combination of both and found that they produce analgesia in chronic neuropathic pain. He used 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3. 3% doxepin and 0.025% capsaicin. The results showed “Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin.”

CORTICOSTEROIDS

Corticosteroids have been used extensively to treat pain and associated symptoms in various types of cancer. They can provide a variety of beneficial effects including: mood elevation, anti-inflammatory activity, antiemetic, appetite stimulant, reduction of cerebral or spinal oedema (reducing spinal compressive problems and acutely raised intracranial pressure).

Bruera et al([vi])demonstrated the analgesic effects of corticosteroids and various authors have described their effect on improving quality of life.

There are 2 different drugs which may be used: dexamethasone and prednisolone. Dexamethasone is given at 16-24mg/day or prednisolone 60-100mg/day for treatment of lumbosacral plexopathy(high dose to help reduce spinal cord oedema). However, patients may respond favourably to a small dose such as dexamethasone 1-2 mg daily for other pain problems. Alternatively, short-term high dose therapy such as 100mg dexamethasone reducing to 96 mg divided into 4 doses a day, tapered down within 2-3 weeks, can be helpful in very severe intractable neuropathic pain. High doses should only be given internittently and can be tapered down over weeks(rapid withdrawal may precipitate pain), with a concurrent administration of an alternative analgesic. High doses are more likely to lead to adverse effects.These may be serious and they increase in severity with prolonged use.

Adverse effects include: muscle wasting, hyperglycaemia (raised blood sugar), weight gain, oedema (fluid retention), indigestion(increased risk of peptic/duodenal ulcer), hypertension(raised blood pressure), adrenal suppression, increased susceptibility to infections, bruising, avascular necrosis of femoral head (damage to thigh bone at hip joint). Also, high doses may precipitate mental disturbances: euphoria is common and not usually problematic (may indeed be therapeutic) but more serious problems such as paranoid psychosis, depression and risk of suicide may occur.

Epidural steroid injections and other local steroid injections (facet joint, trigger point) may be given but invasive spinal procedures are considered by the Arachnoiditis Trust to be potentially damaging: the benefit: risk ratio is poor. The NNT is 7.3 for greater than 75% pain relief in the short-term(1-60 days) and 13 for greater than 50% pain relief in the long-term(12weeks to one year). Looking at NNTs, in comparison with other forms of analgesia, epidural steroids are much less effective. The preservatives in most preparations of steroid injectate may be neurotoxic and there is a risk of causing arachnoiditis, an incurable spinal condition which causes severe, intractable nerve pain and a variety of other symptoms. This issue is addressed more fully in other articles.

CCK ANTAGONISTS

These have also been looked at in a previous article on Opioid medication for neuropathic pain. It has been found that elevation of the anti-opioid peptide cholecystokinin(CCK) is one of the likely causes of incomplete analgesia with opioid medication. This has been demonstrated in animal studies([vii]). Nerve injury results in a rise in plasma CCK([viii]) so that administration of an antagonist such as proglumide (originally developed as an anti-ulcer drug) may effect a return to the pain being opiate-responsive. McCleane([ix]) has found that proglumide can augment the analgesia from sustained-release morphine for neuropathic pain. CCK is also raised by chronic opioid use and may contribute to development of tolerance.( [x])Watkins et al( [xi]) have shown that proglumide can potentiate opiate analgesia and reverse morphine tolerance. More studies need to be done to determine the best clinical use of these findings.

TREATMENT OF VISCERAL PAIN

Painful bladder or rectal spasms may occur in some conditions.

For painful bladder spasms, non-steroidal anti-inflammatory drugs(NSAIDs: discussed in a separate article) may be helpful due to the possible role that prostaglandins play in bladder muscle contraction.

Painful rectal spasms may respond to diltiazem, a calcium channel blocker that reduces smooth-muscle contraction, which has been effective in the management of proctalgia fugax(shooting pains in the rectum). ([xii])Chlorpromazine(a neuroleptic) ([xiii]), and benzodiazepines ([xiv]) have also been used and their efficacy noted anecdotally.

TREATING EXACERBATIONS OF CHRONIC PAIN

Exacerbations of chronic pain may cause patients to present to the emergency department with acute episodes, commonly of back or abdominal pain. Of course, there may also be acute conditions which occur that are unrelated to the chronic condition, or post-operative analgesia is required.

In this situation, the usual medication is insufficient to provide analgesia but will interact with any treatment given for the acute condition. If the patient is on opiate medication, they will have developed tolerance to the effect not only of the medications they are taking, but also a degree of cross-tolerance to the effect of other opioid drugs. This cannot necessarily be accurately predicted as it will vary between individuals. It is not within the scope of this article to address the complexities of prescribing under these conditions.

However, it is worth noting Mehl-Madrona’s study published last year([xv]). This looked at use of a combination of keterolac and chlorpromazine to replace the more usual meperidine/promethazine combination in the emergency room for exacerbations of chronic pain. Keterolac is a potent Non-steroidal anti-inflammatory drug (NSAID) that is indicated for moderate to severe pain (NOT mild pain), chlorpromazine is a neuroleptic(see above). Meperidine (pethidine) is a short-acting opiate given intramuscularly and promazine is given to prevent nausea and vomiting which may be induced by meperidine.

Patients were given either intramuscular doses of 60mg keterolac +50-75 mg chlorpromazine(KET-CHLOR) (depending on weight) or 50mg meperidine plus 25-50mg promethazine(MEP-PROM). (heavier patients were given 1.5 doses). It was found that the pain relief of the 2 different protocols was comparable, but the KET-CHLOR patients had fewer side effects and this combination worked better for nausea(chlorpromazine is a more potent antiemetic than promazine).

Although the author did not refer specifically to the problems of previous tolerance, the study suggests that using a NSAID may be sufficiently effective to negate the need to use extra opiate medication in addition to the patient’s usual regime.