Perhaps the most contentious issue is whether any pharmacological treatment can help relieve painful symptoms of neuropathy.
The WHO pain analgesic ladder is a stepwise approach to pain management related to pain severity — beginning with simple analgesics (paracetamol or NSAIDS), then adding a weak opiate, such as codeine, moving onto stronger opiates if that doesn’t work. But, these seem to be ineffective for neuropathic pain, at least when given on their own. This may even be true of the more potent opiates.
“In our experience morphine is not very good for neuropathic pain,” said Dr Harries.
So many neurologists and palliative experts recommend adding a variety of adjuvants, including topical analgesics (lidocaine, low dose capsaicin cream, 0.075%, topical chloroform), but especially the tricyclic antidepressants (amitriptyline, desipramine, etc), and the anticonvulsant agents (including carbamazepine but especially the new drugs, gabapentin and lamotrigine). Some of these drugs have proven to be effective in treating other neuropathic pain, such as diabetic peripheral neuropathy, which has led to the development of the Analgesic Ladder for Neuropathic Pain.
Unfortunately, clinical evidence in support of using these adjuvants in HIV disease is quite weak.
“This is one of the areas of HIV and treatment which abounds with myths and legends with regards to its treatment. And most of the commonly used treatments, in fact, work not at all,” said Dr Steven Miller of the Innovir Institute in Johannesburg, South Africa, speaking about management of peripheral neuropathies at the International HIV Conference in Botswana in 2006.
Case in point: the tricyclic antidepressants, including desipramine, doxepin, imipramine, nortriptyline, but especially amitryptiline, are widely used for peripheral neuropathy with other causes. Doses usually start at around 25-75mg at night, and titrated up (if side-effects are tolerated) to a maximum dose of 300 mg/day.
But at least two randomised controlled studies show that amitryptiline is no better than placebo in people with HIV and sensory neuropathy.11, 12
In the first study, Kieburtz et al compared amitriptyline, mexiletine and placebo in 145 patients. The second study, by Shlay et al was also a three-way comparison between amitriptyline, acupuncture and control point (feigned acupuncture) in 250 people with HIV-associated peripheral neuropathy. All groups improved somewhat, but there were no significant differences between them. The authors speculated that the control point did have some beneficial effect and thus was not a true placebo. But there may have been other problems with these studies which render their conclusions suspect.
“The amitriptyline trials were not well designed: they were stopped early and underpowered,” Professor Brew told HATIP. However, those studies took place over 10 years ago, and no one’s bothered to re-examine the drug’s usefulness for this indication.
Meanwhile, other drugs used for other causes of neuropathic pain, the anticonvulsants carbamazepine and phenytoin, cannot be given to patients who are taking antiretroviral therapy because they reduce blood concentrations of efavirenz/nevirapine, and protease inhibitors.13
When he was speaking in Botswana, the only symptomatic treatment that Dr Miller showed any hope for were the newer anticonvulsants. “Consistently in the clinic we see that the only compounds which consistently give relief are the newer anti-convulsants: lamotrigine, gabapentin, topiramate for some people,” he said. He added that there are generic preparations of lamotrigine, making it more affordable.
Data on these drugs since that time have been rather mixed.
Early data were promising for lamotrigine (25 mg alternate days for two weeks then dose escalation over seven weeks to a target dose of 400 mg/day), though there was a very high drop-out rate in the study drug arm.14 A subsequent randomised study went up to 400 mg per day (600 mg if another medication which might lower lamotrigine concentrations was used, such as rifampicin), followed by a maintenance phase for HIV-associated painful sensory neuropathies.15 But it could find no clear benefit over placebo in pain scores at the end of the maintenance phase of the study. The authors did report a significant difference in some indicators, such as the slope of improvement for people with ATN and perception of improvement.
However, a recent Cochrane review of the performance of lamotrigine for neuropathic pain (from various causes) in a large number of studies concluded that the routine use of the drug “is unlikely to be of benefit in chronic pain conditions included in this review, or neuropathic pain (pain due to nerve damage).”16 Furthermore, the authors noted that the incidence of rash on the drug was “not trivial.”
Gabapentin looked good in a small randomised, double-blind placebo-controlled study in 26 patients with HIV sensory neuropathy.17 Fifteen patients received gabapentin at 400mg per day before being increased to 1200mg per day over 2 weeks. This dose was maintained or increased to 2400mg per day if not beneficial. There was a significant decrease in pain score in the gabapentin group (-44%) but not the placebo group (n = 11; -30%) — initially at least. It also helped people sleep, in fact, somnolescence was reported in 80% of the gabapentin group. A review in 2003 concluded that the drug was effective for a number of types of neuropathic pain, though doses up to 3600 mg/d may be needed in some patients.18
Unfortunately, at the World AIDS Conference in Mexico City in 2008, Dr David Simpson of Mount Sinai Hospital in New York presented a large randomised, double-blind, placebo-controlled, multicentre trial of the very closely related pregabalin for HIV related peripheral neuropathy, which proved rather disappointing.19
151 subjects were randomised to each arm. Pregabalin doses were titrated from 150 mg to 600 mg/d BID over the course of two weeks, and then continued at their dose (average 385.7 md/d) for 12 weeks. Surprisingly a large proportion of study participants in both arms felt better. 82.8% of pregabalin recipients rated themselves in one of 3 “improved” categories. So did 66.7% of placebo patients. This difference was not significant. Nor were there any difference in mean pain scores after the first couple of weeks on treatment.
With so much conflicting evidence, the experts don’t always agree on what to recommend. This led to something of a debate on the HATIP panel discussion blog site:
“I have found that amitriptyline does work; so does valproic acid. Opiates also work,” said Professor Bruce Brew of the University of New South Wales.
"I think it is important to consider the principles of pain management, [and] that amitriptyline is an adjuvant drug in managing neuropathic pain. It is not in itself an analgesic. It should be combined with an analgesic to provide pain control, so morphine in severe pain plus amitriptyline in low dose is the combination that we use," said Dr Liz Gwyther of the Hospice Palliative Care Association of South Africa.
“We need to be very careful as the placebo effect is significant with pain treatments. Our anecdotal impressions that drugs work in individuals may be demonstration of placebo action not drug effect. I have stopped prescribing amitriptyline for HIV PN as it was demonstrated by two reasonable quality studies to be no more effective than placebo,” Dr Sarah Cox, of London’s Chelsea and Westminster Hospital told HATIP. “Opioids have not yet been trialled in HIV PN but do have an effect in neuropathic PN and are now my first line.”
“The randomised clinical trials do say that nothing much seems to work for peripheral neuropathy in HIV (whether due to ARVs or HIV itself), but I personally find that it never hurts to try amitriptyline and a multivitamin (all we have here) and switch off offending meds if alternatives exist. Sometimes it works (whether [it’s a] placebo or not),” said Dr Ana-Claire Meyer.
“My 2 cents is that whereas we must respect the evidence in clinical trials as the gold standard, we still must take care of patients and provide the best possible therapy, even if empirically driven. We are working hard on developing and testing better meds,” Dr David Simpson told HATIP.
In fact, Dr Simpson has recently conducted a study that found positive results (a mean 22% reduction in pain scores) for 12 weeks from using a single very high dose capsaicin patch.20 This uses doses much higher (8% capsaicin) than available in creams (0.025% to 0.075% capsaicin). The patch essentially works by desensitising the nerves. The patch itself initially causes pain and is put on following a one-hour application of a topical anaesthetic. This sounds as though it would be a bit difficult to administer in a busy clinic setting, and the patch isn’t available yet.
A number of open label studies have reported subjective reductions in pain using the anti-oxidant acetyl carnitine (L-carnitine). For instance, in an open label study, Hart et al reported that LAC can reverse the loss of nerve fibres from the skin, and reduce mitochondrial toxicity and improve the symptoms of peripheral neuropathy after six months of treatment.21
Howver, in the most recently published study "changes were not observed in objective measures of IENF [nerve fiber] density or mtDNA levels, providing little objective support for use of ALC in this setting," wrote the authors.22 There were improvements in symptoms, but again, this was not a placebo controlled study.
A final approach which is often more readily available — though not legally - is medical marijuana. Several studies have reported positive results from using smoked cannabis for neuropathic pain.23, 24, 25, 26, 27 For instance, Abrams et al conducted a randomised clinical trial that found that smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs a 17% reduction (IQR = -29, 8) on placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). “Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy,” wrote the authors.
The approach has its proponents.“I just want to make the case for medical marijuana to sound stronger and clearer,” Dr Zvi Bentwich, of Rosetta Genomics in Israel, told HATIP. “For the last 10 years I have been involved repeatedly with patients in whom this worked quite impressively! So much so that we succeeded in convincing the Ministry of Health, to adopt it as an official policy once each individual case was brought before a special committee that then decided whether to approve it or not.”
But in settings where governments don’t want to agree to make opiates available, despite their proven benefits for pain, suggesting marijuana is opening a can of worms, to put it mildly. The neurocognitive side-effects of the drug would also be a concern. Still it is hard to begrudge this approach to someone whose pain keeps them awake all night.
But more will need to be done for those patients who must live with pain.
"In contrast to pain management in general, neuropathic pain requires a more rigorous approach, involving a multidimensional bio-psycho-social approach that involves the use of appropriate pharmacological agents, exercise, behavioural therapy, attention to sleep quality, patient education and return to work if possible," wrote Hitchcock, Meyer and Gwyther in their assessment of neuropathic pain in South Africa.26
In industrialised settings, people with peripheral neuropathy that won't heal are referred to physical and occupational therapists. Experts trained at offering people supportive care are rarely if ever available in resource-limited settings. But perhaps countries should begin training more of these cadres of healtchcare workers, as it is evident that the demand for their services will be growing.