Ward 86 Management Recommendations
updated May 2015
Contributors: Cheryl Jay, MD
Mark A. Jacobson, MD
Robert Brody, MD
Distal symmetrical polyneuropathy (DSPN) is a common complication of advanced HIV disease that typically presents with paresthesia and numbness in soles of the feet, or less commonly, in the fingertips. Paresthesia can become painful, especially at night, and can progress proximally in a stocking and glove distribution over time with increased severity of pain if effective antiretroviral therapy (ART) is not initiated. Typical physical findings are symmetric distal loss of vibration, temperature, or light touch sensation in the feet with reduced or absent ankle reflexes. Marked asymmetry or weakness, symptoms that begin in the hands, or bowel or bladder dysfunction are not typical features of DSPN.
The pathogenesis of DSPN is still unclear, though it appears that cytokine dysregulation resulting from uncontrolled HIV replication is a key factor in causing the distal nerve fiber loss observed in this condition. Although effective ART appears to halt the worsening of symptoms, pain may not improve on ART; hence, early diagnosis of DSPN and prompt initiation of ART can have a major impact on quality of life.
DSPN rarely occurs in HIV-infected patients with an absolute CD4 count of >300 cells/µL, unless they are receiving a neurotoxic drug (eg, didanosine, stavudine, isoniazid, vincristine, or long-term dapsone or metronidazole) or if they have a concomitant condition that can cause polyneuropathy such as alcoholism, hypothyroidism, vitamin B12 deficiency, diabetes, or syphilis.
Rule out other causes of neuropathy. The minimum workup should include serum thyroid stimulating hormone (TSH), vitamin B12, rapid plasma reagin (RPR), and hemoglobin A1c, along with assessment of ethanol consumption.
Initiate or change ART if the patient is not virologically suppressed.
Discontinue any neurotoxic medications. Didanosine and stavudine are no longer used as part of first-line ART in the United States, but stavudine can be part of the initial treatment regimens in resource-limited settings. The use of stavudine should be phased out as much as possible in any setting. The appearance of DSPN symptoms in a patient receiving didanosine or stavudine is a clear indication for changing the ART regimen.
Pain control. There are no effective treatments to reverse the neuronal damage leading to DSPN. ART usually stops the disease process from worsening but may not impact the severity of pain. Only a few, small randomized trials of DSPN pain treatment have been published. Our pain management strategy for this condition is a stepwise approach that begins with titrating gabapentin to maximally tolerated dosages to achieve pain control without accompanying toxicity (eg, somnolence).
Gabapentin is a generally well-tolerated anticonvulsant demonstrated in 1 randomized trial to reduce HIV-associated DSPN pain and sleep interference by 40-50%.(1) Our approach is to initiate gabapentin therapy at a dosage of 100-300 mg PO TID if renal function is normal, and titrate the dosage upward at 3-4 day intervals until pain control is achieved or unacceptable toxicity, such as somnolence, occurs. The maximum dosage beyond which benefit is unlikely to occur is 3,600 mg/day in divided doses. A closely related drug, pregabalin, was ineffective when compared with placebo in a randomized trial.
Lamotrigine is another anticonvulsant that has been reported to reduce HIV-associated neuropathic pain when caused by exposure to didanosine or stavudine.(2) The benefit for HIV-associated, non-antiretroviral-associated DSPN is less clear. As with gabapentin, this drug should be started at a low dosage (eg, 25 mg of the extended-release formulation PO once daily) and titrated up weekly. Lamotrigine has significant interactions with valproic acid and its derivatives. If these two drugs are coadministered, the upward titration of lamotrigine should be slower. Rash is a common, dose-limiting side effect.
We have had some success with the tricyclic antidepressant, nortriptyline, dosed initially at 10-25 mg PO before bedtime and titrated up, as needed, to a maximum dose of 150 mg. Drowsiness, orthostasis, and xerostomia are common side effects. In some patients, the tricyclic amitriptyline also has helped, though in our experience side effects occur more commonly with amitriptyline than with nortriptyline.
We also have had some success with baclofen, an antispasticity agent that is used as a second-line agent for neuropathic pain (trigeminal neuralgia) in patients with multiple sclerosis. A typical starting dosage is 10-mg tablets, 1/2 to 1 BID to TID, increasing gradually to 20 mg PO TID as a maximum dosage. Sedation is the major side effect. If discontinuing baclofen, the drug should be tapered off over the course of several weeks, rather than ceased abruptly, in patients taking more than 30 mg daily.
A 2007 Cochrane review of antidepressant use to treat neuropathic pain in adults (eg, from diabetes) cited 3 trials showing evidence for benefit with venlafaxine.(3) Although there is no evidence available regarding efficacy of venlafaxine for HIV-associated neuropathic pain, we have had some success with this drug and have observed better tolerance with venlafaxine than with tricyclic antidepressants. We start with a 37.5 mg dose of the extended-release preparation at bedtime and titrate up weekly, if needed, to a maximum dosage of 375 mg daily. Some patients tolerate this drug better with morning dosing. Blood pressure should be monitored as hypertension has occurred. Other side effects are mostly neurological, and there can be a withdrawal syndrome with abrupt discontinuation.
Smoking cannabis (3.56% tetrahydrocannabinol) cigarettes was reported to reduce chronic HIV DSPN pain by 34% compared with 17% among patients who smoked placebo cannabis cigarettes in a randomized trial.(4) Sedation, anxiety, disorientation, confusion, and dizziness were reported more frequently in the cannabis group than in the placebo group, though no severe adverse effects occurred. We have found this option to be effective for some patients, though it may be problematic in states in which medical marijuana is illegal.
For patients for whom all other options have failed to control pain, long-acting opiates (eg, methadone, extended-release morphine) can be titrated to control pain. Such patients may need an additional short-acting opiate (eg, oxycodone or hydrocodone) for breakthrough pain, especially at night.
Duloxetine is a well-tolerated norepinephrine/serotonin reuptake inhibitor, approved by the FDA for the treatment of painful diabetic neuropathy. There is no randomized trial data in HIV patients to support its use, and we have seen little efficacy with this drug.
Qutenza is an 8% capsaicin patch that was reported to be beneficial for HIV DSPN pain in 1 randomized trial.(5) However, an FDA advisory committee voted unanimously against approving the agent for the indication of HIV DSPN pain. The patch, which costs in the range of $750 per patch, is applied to skin once every 12 weeks for 60 minutes after pretreatment with a topical anesthetic.
- Hahn K, Arendt G, Braun JS, et al; German Neuro-AIDS Working Group. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004 Oct;251(10):1260-6.
- Simpson DM, Olney R, McArthur JC, et al. A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology. 2000 Jun 13;54(11):2115-9.
- Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454.
- Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007 Feb 13;68(7):515-21.
- Simpson DM, Brown S, Tobias J; NGX-4010 C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008 Jun 10;70(24):2305-13.