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Management Recommendations > Neuropathy

Ward 86 Management Recommendations

Diagnosis and Management of HIV-Associated Distal Symmetrical Polyneuropathy

updated July 2017

Contributors: Robert V. Brody, MD
Ed Lor, PharmD
Mark A. Jacobson, MD
Cheryl Jay, MD

  1. 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. 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.

  2. 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 may halt the worsening of symptoms, pain may not improve on ART; hence, early diagnosis of DSPN and prompt initiation of ART can prevent future impact on quality of life.

  3. 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.

  4. Management

    1. 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.

    2. Initiate or change ART if the patient is not virologically suppressed.

    3. 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 avoided 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.

    4. 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 assessing the patient's psychological profile and deciding whether to initiate an antidepressant or an antiepileptic as first-line therapy (see Figure, below). If a patient with DSPN pain is depressed or anxious or having difficulty sleeping for whatever reason, we start with an antidepressant (unless the depression is bipolar, in which case we start with an antiepileptic mood stabilizer). Otherwise, we initiate an antiepileptic. Decreasing pain and increasing function of patients with severe DSPN often will require antidepressants, antiepileptics, and conventional analgesics in combination.

      1. Antidepressants for DSPN pain. Our first choice is a norepinephrine/serotonin reuptake inhibitor (SNRI). If this is ineffective or not tolerated, we try a tricyclic antidepressant.

        1. Venlafaxine is the most effective SNRI in our experience. 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.(1) 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.

        2. Duloxetine is a well-tolerated SNRI, approved by the FDA for the treatment of painful diabetic neuropathy. There are no randomized trial data in HIV patients to support its use. Although we have seen less efficacy with this drug than with venlafaxine, duloxetine is less likely to cause withdrawal when stopped suddenly.
        3. 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 although, in our experience, side effects occur more commonly with amitriptyline than with nortriptyline. For patients with severe sleep problems, we will titrate doxepin, starting with a 25 mg dose at bedtime.
      2. Antiepileptics for DSPN pain.

        1. Gabapentin is our first choice. It is a generally well-tolerated anticonvulsant. In one randomized trial, gabapentin reduced HIV-associated DSPN pain and sleep interference by 40-50%.(2) 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 is 3,600 mg/day in divided doses, although some patients can tolerate and benefit from higher doses. A closely related drug, pregabalin, was ineffective when compared with placebo in a randomized trial.
        2. Because many patients become sedated or cannot concentrate while they are taking gabapentin, our next go-to antiepileptic is topiramate. It has the advantage of twice-a-day dosing, mood stabilization, migraine prophylaxis, and possibly utility in decreasing alcohol craving and promoting weight loss. We initiate topiramate at 25 mg BID, titrating to a maximum of 400 mg per day.
        3. Lamotrigine is another anticonvulsant that has been reported to reduce HIV-associated neuropathic pain when caused by exposure to didanosine or stavudine.(3) The benefit for HIV-associated, nonantiretroviral-associated DSPN is less clear. This drug should be started at a low dosage (eg, 25 mg BID) and titrated up weekly as tolerated to a maximum of 400 mg per day. 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. Drug fever may occur, and Stevens-Johnson syndrome has been reported.
        4. Other antiepileptics, such as divalproex sodium (Depakote), tiagabine, or zonisamide, are unproven but may be useful. We do not use carbamazepine because of its many drug-drug interactions with antiretrovirals.
      3. Other options for DSPN pain control.
        1. Baclofen, an antispasticity agent that is a second-line agent for neuropathic pain (trigeminal neuralgia) in patients with multiple sclerosis, may help if there is an element of muscle spasm. A typical starting dosage is 5-10 mg BID to TID, increasing gradually to 20 mg PO 4 times a day 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.
        2. 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. Cannabis edibles and teas also may be useful.
        3. Long-acting opiates (eg, extended-release morphine) may be useful, if the other approaches outlined above in combination are ineffective in increasing the patient's functioning. In such patients, an additional short-acting opiate (eg, oxycodone or hydrocodone) may be needed for breakthrough pain.
        4. Lidocaine ointment has been useful for some patients.
        5. 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 US$750 per patch, is applied to skin once every 12 weeks for 60 minutes after pretreatment with a topical anesthetic.

Figure.

References

  1. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454.
  2. 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.
  3. 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.
  4. 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.
  5. 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.