Tramadol Challenge for Relief of Intractable Central Poststroke Pain

Abstract

To the Editor: Since Dejerine and Roussy's description in 1906,1Dejerine J Roussy G Le syndrome thalamique.Rev Neurol (Paris). 1906; 14: 521-532Google Scholar central poststroke pain (CPSP) has been identified as one of the most intractable pain syndromes. Although several pharmacological agents have been reported to alleviate CPSP partially, complete pain reduction has remained elusive. We report complete cessation of intractable CPSP with use of oral codeine and milnacipran after a successful drug challenge test with tramadol. Report of a Case. A 75-year-old man was evaluated at our pain clinic for CPSP, manifesting as intractable left arm pain of 10 years' duration. The pain had not responded to trials of carbamazepine or amitriptyline. After confirming that a test dose of thiopental (50 mg intravenously) had no effect on the patient's pain symptoms, we administered a 50-mg intravenous infusion of tramadol (a centrally acting analgesic with both narcotic and nonnarcotic mechanisms of action) over 15 minutes. The tramadol produced complete relief of pain for approximately 5 hours. In view of these positive results, we initiated a 6-day trial of oral codeine phosphate (20 mg) and milnacipran (25 mg) twice daily. The pain was completely relieved during the 6-day treatment trial but recurred on the seventh day (ie, the first day after treatment cessation). The medication regimen was reinitiated on the morning of the eighth day, and the painful symptoms disappeared by noon. The patient has experienced no symptoms in the 10 months that he has been taking codeine phosphate and milnacipran. Discussion. Although the mechanism underlying CPSP has not been elucidated fully, functional and diffusion magnetic resonance imaging studies suggest a role of damage to lateral nociceptive thalamoparietal fibers and increased activity in the anterior cingulate and posterior parietal regions of the brain.2Seghier ML Lazeyras F Vuilleumier P Schnider A Carota A Functional magnetic resonance imaging and diffusion tensor imaging in a case of central poststroke pain.J Pain. 2005; 6: 208-212Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Thalamoparietal lesions may also contribute to ongoing CPSP.3Soria ED Fine EJ Disappearance of thalamic pain after parietal subcortical stroke.Pain. 1991; 44: 285-288Abstract Full Text PDF PubMed Scopus (30) Google Scholar Cingulate or posterior parietal brain regions may regulate the responses to chronic nociceptive activity and the downstream pain perceptions modulated by opioidergic circuits.4Vogt BA Wiley RG Jensen EL Localization of Mu and delta opioid receptors to anterior cingulate afferents and projection neurons and input/output model of Mu regulation.Exp Neurol. 1995; 135: 83-92Crossref PubMed Scopus (85) Google Scholar Reduced opioid receptor binding within the pain processing circuits may have some bearing on the unreliable effects of morphine for treatment of CPSP.5Willoch F Schindler F Wester HJ et al.Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study.Pain. 2004; 108: 213-220Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar In our patient, a drug challenge with tramadol abolished the long-term pain. However, it was unclear which one of the drug's 2 mechanisms, moderate stimulation of μ-opioid receptors or enhancement of the descending pain control mechanism, was predominant in the patient's pain relief. To mimic both mechanisms, we administered oral codeine, a moderate μ-opioid receptor agonist, and milnacipran, a serotonin and norepinephrine reuptake inhibitor.6Kimura M Kanetani K Imai R Suzuki H Isayama K Endo S Therapeutic effects of milnacipran, a serotonin and noradrenaline reuptake inhibitor, on post-stroke depression.Int Clin Psychopharmacol. 2002; 17: 121-125Crossref PubMed Scopus (30) Google Scholar We observed not only sustained pain relief during the course of treatment but also recurrence of CPSP when the medications were discontinued. These observations, in conjunction with the negative results of the thiopental test, suggest that the pain reductions by tramadol, and subsequently with codeine plus milnacipran, were not placebo effects. Rather, the costimulation of μ-opioid receptors and descending pain control mechanisms may represent a new strategy for the treatment of intractable CPSP.