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Enduring pain
   Last updated: 27.10.04
Neuropathy is still getting on many people’s nerves, by Edwin J Bernard
Despite the many advances in the treatment of HIV disease, neuropathy, or nerve damage - often experienced as tingling, numbness or burning sensations in the feet, legs and/or hands - remains the most common cause of pain in those living with HIV, experienced by more than one-in-three at some point in their lives. This is unsurprising given that neuropathy is caused both by HIV itself and by some of the drugs used to treat it , particularly the NRTIs known as the “d-drugs” – ddC, ddI and d4T - although some experts think that 3TC may also occasionally cause neuropathy.
Given the wide range of antiretrovirals available in the UK today, it is now usually possible to avoid the use of these neurotoxic NRTIs. However, individuals currently experiencing persistent neuropathy currently have few choices for pain relief, and it is rare for the pain to resolve completely. Happily, promising new treatments were recently unveiled at the Eleventh Retroviruses Conference in San Francisco (see ‘Pleasure and pain’) and an ongoing study of acetyl-l-carnitine at London’s Royal Free looks promising.
ATU recently spoke with Dr Hadi Manji, one of only a handful of neurologists in the UK with extensive clinical experience of HIV-related neuropathy. Based at Ipswich Hospital, Dr Manji runs an HIV-related neuropathy clinic at London’s Mortimer Market Centre, as well as a general neuropathy clinic at The National Hospital for Neurology and Neurosurgery in London’s Queen Square.


Which factors put people with HIV at a higher risk of experiencing neuropathy?
HM: Broadly speaking, I see two groups of patients; people infected in the Eighties who have been on antiretroviral therapies for a long time, and people, mostly from outside Europe, who have been diagnosed late, when their HIV has already progressed to AIDS, and have a neuropathy due to HIV itself.

How can you tell if the neuropathy is caused by HIV or by the medicines used to treat it?
HM: The presentation of HIV neuropathy is very similar to drug-related neuropathy, but there are some clues to tell whether it is the drugs or not. Sometimes the drug-related neuropathies come on very rapidly, almost explosively, and that would alert you as to whether it is drug-related. My impression is that drug-related neuropathies may be more painful. And if there’s involvement of the fingers, that, to my mind, would be more drug- than HIV-related.

How many people have both HIV and drug-related neuropathy together?
HM: In my experience, a lot of people - up to 60% - who develop neuropathy that is attributed to the drugs are still left with neuropathy when they stop the offending drug, despite some improvement. My feeling is that these individuals probably had asymptomatic HIV neuropathy that was unmasked by the drugs.

What other factors can make neuropathy worse?
HM: The bottom line would be, if you’ve got nerve-related problems for whatever reason - HIV or antiretrovirals - and you add another factor that damages nerves, you are more likely to cause further damage. For example, when I see patients, I ask about alcohol intake, because alcohol damages nerves, making you more vulnerable to neuropathy.

How much alcohol is too much?
HM: It would seem reasonable that anyone who drinks more than the recommended 21 units a week for men [14 for women] may be more vulnerable. It’s impossible to be categorical about these things because the other factor in alcohol-related neuropathy would be vitamin B deficiency due to poor diet.

Does that also mean that people who use recreational drugs, and have a poor diet, could get neuropathy?
HM: There’s no evidence that recreational drugs themselves cause neuropathy. However, the poor nutrition that can accompany drug-taking could certainly be a factor, since it is deficiency of the B vitamins which is important for nerve function. The cause of neuropathy in people who eat badly for any reason is usually thiamine (vitamin B1) deficiency.

Would you suggest that people whose diet is likely to be poor, for whatever reason, supplement with a vitamin B-complex tablet?
HM: I think that’s reasonable, but with a caveat. One of the B-complex vitamins, B6, if taken in excess, causes neuropathy. At one stage in New York, B6 overdose was a common cause of neuropathy, because people were taking too much in their supplements. It’s also worth checking B12 levels if you’re a vegetarian, or if you have chronic diarrhoea.
[For more on vitamin B supplements see ‘B-ing prepared’]


What else do you check for when you see your patients for the first time?
HM: Diabetes is a cause of neuropathy, so I always check my patients’ blood sugar. I also check to see if there are any other drugs that could cause neuropathy. For example, isoniazid, which is used to treat TB, can cause neuropathy.

What about co-infection with hepatitis C?
HM: Although there is a mechanism by which hepatitis C can cause neuropathy, it is very rare. I haven’t seen more neuropathy in co-infected patients.

Are all the d-drugs equally likely to cause neuropathy, and of all the HAART medications, is it only d-drugs that can cause neuropathy?
HM: Of the antiretrovirals, only ddC, ddI and d4T are associated with neuropathy. The others aren’t. ddC used to be the worst offender, but use of that drug has reduced significantly. In fact, compared with the early studies, incidence of neuropathy from all of these drugs is reducing for two reasons. First, lower drug doses are being used. Secondly, people aren’t quite so immunosuppressed when they start the drugs, so they don’t run the risk of this asymptomatic HIV neuropathy, as it is less likely to occur in people with higher CD4 counts.

How do you treat people with neuropathy who have no option but to remain on d-drugs?
HM: Often, if the person is doing well as far as CD4 count and viral load, both patient and HIV doctor are not that keen on stopping the d-drug. You could consider reducing the dose of the offending drug, but then there are concerns about resistance. Otherwise, all we can do then is to control the symptoms by using other drugs to make life a bit more bearable.

What drugs do you prescribe to treat the pain of neuropathy?
HM: First line, I tend to prescribe, for symptomatic treatment, an anti-epileptic drug called gabapentin. It’s been shown to be helpful in diabetic neuropathy, which is not dissimilar to HIV-related neuropathy. It doesn’t have many side-effects and doesn’t interfere with antiretrovirals. There have been no placebo-controlled trials for gabapentin for people with HIV, although we are actually running one at Mortimer Market in conjunction with Barts and the London Hospital. I find gabapentin works for some of my patients, but not all of them. Second choice is another anti-epileptic drug, lamotragine, for which there is some evidence of benefit.

What about acetyl-l-carnitine?
HM: A 2001 study by Simpson and colleagues found that there was no difference in acetyl-l-carnitine levels in those who had neuropathy and those who didn’t. I have no problems if people want to try acetyl-l-carnitine, since it has no side-effects, and for some people it has made a difference. I think its important to bear in mind, for all the neuropathy ‘remedies’ that where clinical trials have not found a clear benefit - like acupuncture or acetyl-l-carnitine - that doesn’t always mean that it won’t have some sort of benefit in some individuals, since pain is very subjective. People’s pain thresholds vary and how the pain affects their lives is also different.
[Editor’s note: Positive results from a study at London’s Royal Free will soon be published in the journal AIDS that found acetyl-l-carnitine significantly regenerated peripheral nerves damaged by NRTIs over two years.]

Do you prescribe antidepressants?
HM: I think they have a role to play, so I wouldn’t write them off completely. I tend to use one of the tricyclics, amitryptyline. The crucial thing is to start at the lowest possible dose (10mg), since it causes drowsiness. However, this does work in the patients’ favour, particularly if they take it at night, because they can get a decent night’s sleep.

Given the promising pain-reducing qualities of smoked marijuana presented at the recent Retroviruses Conference, would you support its use in the UK?
HM: In terms of other neuropathies, I have had patients who have said that smoking cannabis may be helpful. These results from San Francisco are preliminary, and it’s never been trialled in a formal setting. Since there is no definite evidence to its benefit, I currently wouldn’t be able to recommend it.

Before HAART, about one third of people reported HIV-related neuropathy. Why hasn’t the incidence of neuropathy decreased in the HAART era?
HM: It’s a combination of people living longer, and use of the d-drugs. We may see even more neuropathies appear as people with HIV are living longer. This is because there may well be increased risks for other causes of neuropathy that we currently see in non-HIV peripheral nerve clinics: diabetes, for example. So, when doctors see patients who are ageing with HIV, they will have to consider not just HIV or the drugs they take, but the other causes, too.

B-ing prepared
Vitamin B deficiency can cause neuropathy, but too much vitamin B6 (pyridoxine) can cause it too, so how much is just right? The British National Formulary conservatively suggests no more than 10-20mg a day. However, the Food and Nutrition Board of the US Institute of Medicine has established an upper tolerable intake level for vitamin B6 of 100mg a day. A report in the New England Journal of Medicine found that doses between 200mg and 5 grams a day resulted in painful - but reversible - neuropathy.1


Pleasure and pain
A team of researchers from San Francisco have found that smoking marijuana three times a day for a week reduced the pain of HIV-related neuropathy by at least 30% in ten out of 16 cases.
Fourteen men and two women, all experienced marijuana users with long-standing HIV disease (an average thirteen years) and suffering from either HIV neuropathy (n=3), d-drug neuropathy (n=8), or both (n=5) for an average of six years, smoked cigarettes containing 3.56% THC (the active ingredient in marijuana).2
A randomised, placebo-controlled study is now recruiting 50 people in San Francisco to attempt to confirm these preliminary findings.
Another small study of people with HIV-related neuropathy found that a one-hour application of a patch that contains a high concentration of capsaicin - the ‘heat’ from red hot chilli peppers - reduced pain by at least 30% over 12 weeks in eight out of the twelve participants. It did this by temporarily destroying nerve fibres under the skin, reducing sensitivity to temperature, without significantly affecting any other functions.3
Unfortunately, the patch is currently only available in US clinical trials.


Key Conclusions
  • Neuropathy is a significant cause of pain for people with HIV

  • It can be made worse by certain HAART medications, notably the d-drugs, ddI, d4T and ddC

  • If you can avoid or switch from d-drugs without it adversely affecting the potency of HAART, it may be wise to do so

  • There are drugs that can help relieve the pain, but they don’t always work

  • Acetyl-l-carnitine may reverse nerve damage, but more trials are needed to be sure

  • Neuropathy due to other causes, like diabetes or treatment for TB, may also occur in HIV-positive people

  • Too much alcohol or a poor diet can make the pain worse, but taking a vitamin B supplement may help



References
1. Schaumburg H, et al. N Engl. J Med 309 (8): 445-8, 1983.
2. Jay C, et al. 11th CROI, San Francisco, abstract 496, 2004.
3. Simpson D, et al. 11th CROI, San Francisco, abstract 490, 2004.