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Letters| Volume 26, ISSUE 6, P1073-1074, December 2003

Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain

      To the Editor:
      Benzodiazepines are used widely in medical practice, especially as anxiolytics and anticonvulsants. Benzodiazepines are thought to affect neural processing by influencing gamma-aminobutyric acid (GABA)-mediated inhibition of nerve impulses. It is believed that benzodiazepines may similarly inhibit some of the ectopic activity in peripheral nerves following nerve injury and this has led to the use of benzodiazepines in the management of neuropathic pain.
      • Reddy S.
      • Patt R.B.
      The benzodiazepines as adjuvant analgesics.
      Particular attention has been paid to the benzodiazepine clonazepam, which some small trials have demonstrated to be effective in several neuropathic pain syndromes.
      • Smirne S.
      • Scarlato G.
      Clonazepam in cranial neuralgias.
      • Young R.J.
      • Clarke B.F.
      Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs.
      • Bartusch S.L.
      • Sanders B.J.
      • D'Alessio J.G.
      • Jernigan J.R.
      Clonazepam for the treatment of lancinating phantom limb pain.
      • Herman C.R.
      • Schiffman E.L.
      • Look J.O.
      • Rindal D.B.
      The effectiveness of adding pharmacologic treatment with clonazepam or cyclobenzaprine to patient education and self-care for the treatment of jaw pain upon awakening: a randomized clinical trial.
      • Court J.E.
      • Kase C.S.
      Treatment of tic douloureux with a new anticonvulsant (clonazepam).
      As there is currently no evidence for the use of clonazepam in cancer pain, we undertook a preliminary, prospective case-series to assess the use of clonazepam as an adjuvant analgesic in patients with cancer related neuropathic pain.

      Methods and results

      Over a four-month period, consecutive inpatients admitted to a specialist palliative care unit with a history of cancer-related neuropathic pain only partially responsive to opioid therapy were monitored for pain control when titrated onto clonazepam as an adjuvant analgesic by their treating clinician. The diagnosis of neuropathic pain was made if patients described burning pain, paroxysmal episodes of shooting pain or allodynia. According to agreed unit guidelines, clonazepam was started orally at a dose of 0.5 mg on Day 0, increased to 1 mg on day one and increased to 2 mg on Day 4 according to response and side effects. Using four-point rating scales, pain and drowsiness were scored daily for five days (0 = absent, 1 = mild, 2 = moderate, 3 = severe).
      Ten patients were titrated onto clonazepam. Five patients were excluded from analysis. Two of those patients stopped clonazepam due to drowsiness on Day 2, and three were excluded due to an increase of their regular opioid dose during clonazepam titration. For five patients, complete data were available from Day 0 to Day 5. Cancer diagnosis, pain syndrome diagnosis, clonazepam and opioid dose, and pain and drowsiness score for each patient on Day 0 and Day 5 are reported in Table 1. All patients were female. The mean age was 54.4 years (SD 11.2 years, range 44 to 73 years). The median dose of clonazepam on day 5 was 1 mg. The pain score improved in all patients and decreased from a median of three (range 2 to 3) on Day 0 to one (range 0 to 2) on Day 5. Two of the five patients reported drowsiness.
      Table 1Cancer Diagnosis, Pain Syndrome, Clonazepam and Opioid Dose, Pain and Drowsiness Scores Day 0 and Day 5
      Pt.DiagnosisPain SyndromeClonazepam Dose Day 5 (mg/day)Opioid Dose
      Daily morphine equivalent. The dose of opioid remained unchanged from Day 0 to Day 5.
      (mg/day)
      Pain Score Day 0Pain Score Day 5Drowsiness Score Day 0Drowsiness Score Day 5
      1.OvaryLumbar Radiculopathy1 mg60 mg3202
      2.CervixSacral Plexopathy0.5 mg140 mg3103
      3.BreastSpinal Cord Compression2 mg60 mg2100
      4.BreastLumbar Radiculopathy1 mg1200 mg3000
      5.LungSacral Radiculopathy1 mg60 mg3200
      a Daily morphine equivalent. The dose of opioid remained unchanged from Day 0 to Day 5.

      Comment

      Neuropathic pain has a relatively poor response to opioids and adjuvant analgesics are, therefore, used commonly in the management of neuropathic pain syndromes.
      • Cherny N.I.
      • Thaler H.T.
      • Friedlander-Klar H.
      • et al.
      Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms.
      • Farrar T.F.
      • Portenoy R.K.
      Neuropathic cancer pain: The role of adjuvant analgesics.
      Our study suggests that clonazepam may be effective as an adjuvant analgesic in cancer-related neuropathic pain. The advantages of clonazepam over other commonly used adjuvant analgesics that have significant side effects and, therefore, require slow dose titration (such as amitriptyline, carbamazepine and gabapentin)
      • Max M.B.
      • Lynch S.A.
      • Muir J.
      • et al.
      Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.
      • Wiffen P.
      • Collins S.
      • McQuay H.
      • et al.
      Anticonvulsant drugs for acute and chronic pain (Cochrane Review).
      may be its simple and rapid titration regimen, as well as its availability for subcutaneous application once the oral route becomes impossible to use. With our titration regimen, all five evaluated patients in the study had a reduced pain score on Day 5.
      According to our unit guidelines, doses of up to 2 mg of clonazepam were used in this case series. These guidelines follow the results of studies of clonazepam in neuropathic pain syndromes in which doses of up to 8 mg of clonazepam were used, but a number of patients developed marked drowsiness.
      • Smirne S.
      • Scarlato G.
      Clonazepam in cranial neuralgias.
      • Court J.E.
      • Kase C.S.
      Treatment of tic douloureux with a new anticonvulsant (clonazepam).
      Despite these lower doses of clonazepam, some patients in the series experienced drowsiness suggesting this to be a limiting side effect when clonazepam is used for cancer-related neuropathic pain.
      The results of this small preliminary study suggest that a randomized, controlled trial about the use of clonazepam as an adjuvant analgesic in neuropathic pain should be performed.

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