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Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans
Neuroscience Letters 343 (2003) 144–146 www.elsevier.com/locate/neulet
Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans Brian L. Schmidta, Robert W. Geara, Jon D. Levinea,b,c,d,e,* a
Department of Oral and Maxillofacial Surgery, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA b Department of Anatomy, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA c Department of Medicine, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA d Department of Division of Neuroscience, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA e NIH Pain Center (UCSF), C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA Received 8 January 2003; received in revised form 5 March 2003; accepted 6 March 2003
Abstract We report on the response of medically refractory neuropathic trigeminal pain in three patients to intravenous administration of a combination of the kappa-partial agonist opioid nalbuphine and the opioid antagonist naloxone. Each of the three patients had developed a painful peripheral neuropathy as a complication of chemical or mechanical injury to the trigeminal nerve. Each patient had been tried on a number of analgesics, including mu-opioids, and had not gained relief or was not able to tolerate side effects of the medications. Pain intensity was measured for 3 h following drug administration using a 10 cm visual analog scale. All three patients reported marked decrease in pain following administration of the nalbuphine and naloxone combination. These findings suggest a novel approach to the management for neuropathic pain. q 2003 Published by Elsevier Science Ireland Ltd. Keywords: Kappa opioids; Nerve injury; Local anesthetic toxicity; Opioid antagonism; Anti-analgesia; Dysesthesia
Medical management of painful peripheral neuropathies is a therapeutic challenge. Trigeminal neuropathic pain, like other painful peripheral neuropathies, is generally poorly responsive to currently available therapies [7 – 9]. Agents that might have some limited effect on pain associated with neuropathy include tricyclic antidepressants, antiepileptics, and m-opioids (e.g. morphine). These agents suffer from significant side-effects including mental confusion, constipation and respiratory depression, which further limit their efficacy. Although there is widespread perception that k-opioids are less effective analgesics than m-opioids, and are associated with dysphoria [11], they have been shown to be effective for painful peripheral neuropathy in experimental animal models [2]. There are, to the best of our knowledge, no reports of k opioid efficacy for neuropathic pain in humans. Recently we observed that the k-opioid * Corresponding author. Tel.: þ1-415-476-5108; fax: þ 1-415-476-6305. E-mail address: [email protected] (J.D. Levine).
nalbuphine combined with a low dose of naloxone results in prolonged postoperative analgesia [5]. Therefore, we administered a similar nalbuphine-naloxone combination to a small sample of patients with chronic painful trigeminal neuropathy. In the oral cavity neuropathic pain can result from injection of local anesthetics [9]. Three patients with painful peripheral neuropathy involving the mandibular division of the trigeminal nerve were studied. Each patient discontinued all medications prescribed to treat pain 2 weeks prior to the test date. An intravenous catheter was inserted for drug administration. Pain intensity was measured using a 10 cm visual analog scale (VAS) anchored on the left with the words ‘No Pain’ and on the right with the words ‘Worst Pain Imaginable’. After baseline VAS records were obtained each patient received an open intravenous injection of a mixture of naloxone (0.4 mg) (Abbott Laboratories, Abbott Park, IL) and nalbuphine (5 mg) (Abbott Laboratories, Abbott Park, IL). Both the patient and the research nurse were blinded to the identity of the drug given. VAS pain
0304-3940/03/$ - see front matter q 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0304-3940(03)00356-2
B.L. Schmidt et al. / Neuroscience Letters 343 (2003) 144–146
scores were recorded at 20 min intervals for 3 h following drug administration. The following is a brief clinical description of the three patients: Case 1. A 42-year-old man, 1 year prior to enrollment, received a single right-sided inferior alveolar nerve block consisting of 2% lidocaine with 1:100,000 epinephrine administered with a 30-gauge needle. The injection produced an electric shock-like sensation and shooting pain to the tip of his tongue. For 2 weeks following the injection he reported an abnormal taste; however, as his taste recovered he developed painful dysesthesia in the distribution of the lingual nerve. This pain was at its lowest level upon waking, worsened throughout the day and was significantly enhanced by movement. Sensory testing with von Frey hairs and two-point discrimination demonstrated no difference between the unaffected and affected side. The patient had been previously treated with amitriptyline, neurontin, clonazepam, Celebrex and capsaicin lozengers over the previous 9 months with no relief. Case 2. A 40-year-old woman who received an inferior alveolar nerve local anesthetic block by injection of 2% lidocaine with 1:100,000 epinephrine that produced a severe, sharp pain in the distribution of the nerve. The patient then underwent uncomplicated extraction of her lower left first molar. Subsequent to the injection she was initially anesthetic; however, 15 months prior to the current experiment, the anesthesia was replaced by a dysesthetic sensation described as constant dull pain exacerbated significantly with chewing and hot and cold liquids. Formal neurosensory testing demonstrated no difference between the left and right sides. Treatment included oral narcotics and neurontin, which resulted in difficulty ambulating and dysarthria, as well as inadequate pain relief. Case 3. A 25-year-old woman underwent a root canal procedure involving the lower right first molar. For 24 h following the procedure her sensation was normal; however, she developed a dysesthesia that involved her right lower lip. An X-ray revealed root canal sealant material beyond the apex of the molar that appeared to be in close proximity to the inferior alveolar nerve. The patient underwent exploratory surgery 15 days following the root canal and sealant material was found in contact with the inferior alveolar nerve. Friable tissue consistent with inflammatory material surrounded the nerve. Histopathologic examination of this tissue was consistent with fat necrosis. All foreign material and surrounding inflammatory tissue was removed. Over the next 3 months her lower lip dysesthesia worsened. The patient had taken narcotics, amitriptyline and neurontin with minimal relief and developed significant side effects including ataxia, dysarthria and lethargy. She received the test medication 3 months following the initial dental procedure. Following injection of the nalbuphine-naloxone combination, all three patients reported a decrease in their pain level, experiencing over a 50% reduction in their pain level
145
within 20 min following drug administration (Fig. 1). The magnitude of the analgesia was still maximal in two of the three patients at the end of the experiment 3 h after drug administration. None of the patients complained of sedation throughout the entire experimental period. Two patients developed mild nausea, which did not require treatment. The present study constitutes, to the best of our knowledge, the first report of the effective use of a k-opioid agonist to treat neuropathic pain. Although studied in an open label study in a small number of patients this response is striking since chronic neuropathic pain responds poorly [7 –9], especially to this degree, with available therapeutic interventions and since the patients in this study had been managed unsuccessfully with multiple medications including m-opioid analgesics. We previously reported that nalbuphine produces a sexually dimorphic analgesia with females experiencing significantly better analgesia than males [6]. In fact, the dose of nalbuphine that was used in the current study, when used alone, significantly increased postoperative pain in men. The addition of naloxone reversed this increase in pain and significantly enhanced nalbuphine analgesia in both males and females [5]. Thus, the analgesic potency of a k-opioid/ naloxone combination appears to rely on relatively selective naloxone-mediated antagonism of the anti-analgesic action of the k-opioid. The relative doses of k-opioid and naloxone may be critical in terms of the analgesia produced; thus, we recently observed that altering the dose of nalbuphine in combination with the same dose of naloxone decreases the postoperative analgesic effect significantly (unpublished observations). While nalbuphine’s analgesic and antianalgesic properties might be explained by the drug’s opioid agonist and antagonist properties, respectively, a more likely explanation is agonist activation of an antianalgesic mechanism.
Fig. 1. The effect on pain of the combination of nalbuphine (5 mg) and naloxone (0.4 mg) plotted as changes in pain level over the 3 h following administration. Predrug pain levels are indicated to the left of the arrow at time 2 10 min.
146
B.L. Schmidt et al. / Neuroscience Letters 343 (2003) 144–146
A variety of analgesic agonists, including selective k-opioid agonists and morphine, activate an anti-analgesia system involving the putative endogenous k-opioid agonist dynorphin [3]. Similar to the human data presented here, activation of the antianalgesic actions of dynorphin is antagonized by naloxone [4]. More recent data demonstrates that the mechanism responsible for dynorphin-mediated antianalgesia involves the release of intracerebral interleukin-1b (IL-1b); in fact, dynorphin is not antianalgesic in animals genetically deficient in release of IL-1b [10]. Interestingly, while k-opioid agonists activate a centrally mediated antianalgesic mechanism that can be antagonized by naloxone [4], k-opioid agonist effectiveness with neuropathic-type pain appears to occur through a peripheral mechanism [1]. Such a combination of peripheral and central effects of nalbuphine and naloxone, respectively, might explain the reduction of neuropathic pain observed in the three cases described here. Regardless of the mechanism, the results of the current study raise the possibility of a novel treatment for chronic neuropathic pain. However, a double-blind placebo-controlled study is needed to confirm our findings in these case reports as well as an evaluation of the use of repeated administration in this patient population.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
Acknowledgements This work was supported by NIH grant NR03923.
[10]
[11]
References [1] G. Catheline, G. Guilbaud, V. Kayser, Peripheral component in the
enhanced antinociceptive effect of systemic U-69,593, a kappa-opioid receptor agonist in mononeuropathic rats, Eur. J. Pharmacol. 357 (1998) 171 –178. G. Catheline, V. Kayser, G. Guilbaud, Further evidence for a peripheral component in the enhanced antinociceptive effect of systemic morphine in mononeuropathic rats: involvement of kappa-, but not delta-opioid receptors, Eur. J. Pharmacol. 315 (1996) 135 –143. J.M. Fujimoto, K.S. Arts, J.J. Rady, L.F. Tseng, Spinal dynorphin A (1–17): possible mediator of antianalgesic action, Neuropharmacology 29 (1990) 609 –617. J.M. Fujimoto, J.J. Rady, Intracerebroventricular physostigmineinduced analgesia: enhancement by naloxone, beta-funaltrexamine and nor-binaltorphimine and antagonism by dynorphin A (1–17), J. Pharmacol. Exp. Ther. 251 (1989) 1045–1052. R.W. Gear, C. Miaskowski, N.C. Gordon, S.M. Paul, P.H. Heller, J.D. Levine, Action of naloxone on gender-dependent analgesic and antianalgesic effects of nalbuphine in humans, J. Pain 1 (2000) 122 –127. R.W. Gear, C. Miaskowski, N.C. Gordon, S.M. Paul, P.H. Heller, J.D. Levine, The kappa opioid nalbuphine produces gender- and dosedependent analgesia and antianalgesia in patients with postoperative pain, Pain 83 (1999) 339–345. J. Gregg, Non-surgical management of traumatic neuralgias and sensory neuropathies, Oral Maxillofac. Surg. Clin. N. Am. 4 (1992) 375 –392. W.S. Kingery, A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes, Pain 73 (1997) 123 –139. M.A. Pogrel, S. Thamby, Permanent nerve involvement resulting from inferior alveolar nerve blocks, J. Am. Dent. Assoc. 131 (2000) 901 –907. J.J. Rady, J.M. Fujimoto, Confluence of antianalgesic action of diverse agents through brain interleukin(1beta) in mice, J. Pharmacol. Exp. Ther. 299 (2001) 659– 665. E.M. Zola, D.C. McLeod, Comparative effects and analgesic efficacy of the agonist-antagonist opioids, Drug Intell. Clin. Pharm. 17 (1983) 411 –417.
Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans Brian L. Schmidta, Robert W. Geara, Jon D. Levinea,b,c,d,e,* a
Department of Oral and Maxillofacial Surgery, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA b Department of Anatomy, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA c Department of Medicine, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA d Department of Division of Neuroscience, C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA e NIH Pain Center (UCSF), C-522 (Box 0440), University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA Received 8 January 2003; received in revised form 5 March 2003; accepted 6 March 2003
Abstract We report on the response of medically refractory neuropathic trigeminal pain in three patients to intravenous administration of a combination of the kappa-partial agonist opioid nalbuphine and the opioid antagonist naloxone. Each of the three patients had developed a painful peripheral neuropathy as a complication of chemical or mechanical injury to the trigeminal nerve. Each patient had been tried on a number of analgesics, including mu-opioids, and had not gained relief or was not able to tolerate side effects of the medications. Pain intensity was measured for 3 h following drug administration using a 10 cm visual analog scale. All three patients reported marked decrease in pain following administration of the nalbuphine and naloxone combination. These findings suggest a novel approach to the management for neuropathic pain. q 2003 Published by Elsevier Science Ireland Ltd. Keywords: Kappa opioids; Nerve injury; Local anesthetic toxicity; Opioid antagonism; Anti-analgesia; Dysesthesia
Medical management of painful peripheral neuropathies is a therapeutic challenge. Trigeminal neuropathic pain, like other painful peripheral neuropathies, is generally poorly responsive to currently available therapies [7 – 9]. Agents that might have some limited effect on pain associated with neuropathy include tricyclic antidepressants, antiepileptics, and m-opioids (e.g. morphine). These agents suffer from significant side-effects including mental confusion, constipation and respiratory depression, which further limit their efficacy. Although there is widespread perception that k-opioids are less effective analgesics than m-opioids, and are associated with dysphoria [11], they have been shown to be effective for painful peripheral neuropathy in experimental animal models [2]. There are, to the best of our knowledge, no reports of k opioid efficacy for neuropathic pain in humans. Recently we observed that the k-opioid * Corresponding author. Tel.: þ1-415-476-5108; fax: þ 1-415-476-6305. E-mail address: [email protected] (J.D. Levine).
nalbuphine combined with a low dose of naloxone results in prolonged postoperative analgesia [5]. Therefore, we administered a similar nalbuphine-naloxone combination to a small sample of patients with chronic painful trigeminal neuropathy. In the oral cavity neuropathic pain can result from injection of local anesthetics [9]. Three patients with painful peripheral neuropathy involving the mandibular division of the trigeminal nerve were studied. Each patient discontinued all medications prescribed to treat pain 2 weeks prior to the test date. An intravenous catheter was inserted for drug administration. Pain intensity was measured using a 10 cm visual analog scale (VAS) anchored on the left with the words ‘No Pain’ and on the right with the words ‘Worst Pain Imaginable’. After baseline VAS records were obtained each patient received an open intravenous injection of a mixture of naloxone (0.4 mg) (Abbott Laboratories, Abbott Park, IL) and nalbuphine (5 mg) (Abbott Laboratories, Abbott Park, IL). Both the patient and the research nurse were blinded to the identity of the drug given. VAS pain
0304-3940/03/$ - see front matter q 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0304-3940(03)00356-2
B.L. Schmidt et al. / Neuroscience Letters 343 (2003) 144–146
scores were recorded at 20 min intervals for 3 h following drug administration. The following is a brief clinical description of the three patients: Case 1. A 42-year-old man, 1 year prior to enrollment, received a single right-sided inferior alveolar nerve block consisting of 2% lidocaine with 1:100,000 epinephrine administered with a 30-gauge needle. The injection produced an electric shock-like sensation and shooting pain to the tip of his tongue. For 2 weeks following the injection he reported an abnormal taste; however, as his taste recovered he developed painful dysesthesia in the distribution of the lingual nerve. This pain was at its lowest level upon waking, worsened throughout the day and was significantly enhanced by movement. Sensory testing with von Frey hairs and two-point discrimination demonstrated no difference between the unaffected and affected side. The patient had been previously treated with amitriptyline, neurontin, clonazepam, Celebrex and capsaicin lozengers over the previous 9 months with no relief. Case 2. A 40-year-old woman who received an inferior alveolar nerve local anesthetic block by injection of 2% lidocaine with 1:100,000 epinephrine that produced a severe, sharp pain in the distribution of the nerve. The patient then underwent uncomplicated extraction of her lower left first molar. Subsequent to the injection she was initially anesthetic; however, 15 months prior to the current experiment, the anesthesia was replaced by a dysesthetic sensation described as constant dull pain exacerbated significantly with chewing and hot and cold liquids. Formal neurosensory testing demonstrated no difference between the left and right sides. Treatment included oral narcotics and neurontin, which resulted in difficulty ambulating and dysarthria, as well as inadequate pain relief. Case 3. A 25-year-old woman underwent a root canal procedure involving the lower right first molar. For 24 h following the procedure her sensation was normal; however, she developed a dysesthesia that involved her right lower lip. An X-ray revealed root canal sealant material beyond the apex of the molar that appeared to be in close proximity to the inferior alveolar nerve. The patient underwent exploratory surgery 15 days following the root canal and sealant material was found in contact with the inferior alveolar nerve. Friable tissue consistent with inflammatory material surrounded the nerve. Histopathologic examination of this tissue was consistent with fat necrosis. All foreign material and surrounding inflammatory tissue was removed. Over the next 3 months her lower lip dysesthesia worsened. The patient had taken narcotics, amitriptyline and neurontin with minimal relief and developed significant side effects including ataxia, dysarthria and lethargy. She received the test medication 3 months following the initial dental procedure. Following injection of the nalbuphine-naloxone combination, all three patients reported a decrease in their pain level, experiencing over a 50% reduction in their pain level
145
within 20 min following drug administration (Fig. 1). The magnitude of the analgesia was still maximal in two of the three patients at the end of the experiment 3 h after drug administration. None of the patients complained of sedation throughout the entire experimental period. Two patients developed mild nausea, which did not require treatment. The present study constitutes, to the best of our knowledge, the first report of the effective use of a k-opioid agonist to treat neuropathic pain. Although studied in an open label study in a small number of patients this response is striking since chronic neuropathic pain responds poorly [7 –9], especially to this degree, with available therapeutic interventions and since the patients in this study had been managed unsuccessfully with multiple medications including m-opioid analgesics. We previously reported that nalbuphine produces a sexually dimorphic analgesia with females experiencing significantly better analgesia than males [6]. In fact, the dose of nalbuphine that was used in the current study, when used alone, significantly increased postoperative pain in men. The addition of naloxone reversed this increase in pain and significantly enhanced nalbuphine analgesia in both males and females [5]. Thus, the analgesic potency of a k-opioid/ naloxone combination appears to rely on relatively selective naloxone-mediated antagonism of the anti-analgesic action of the k-opioid. The relative doses of k-opioid and naloxone may be critical in terms of the analgesia produced; thus, we recently observed that altering the dose of nalbuphine in combination with the same dose of naloxone decreases the postoperative analgesic effect significantly (unpublished observations). While nalbuphine’s analgesic and antianalgesic properties might be explained by the drug’s opioid agonist and antagonist properties, respectively, a more likely explanation is agonist activation of an antianalgesic mechanism.
Fig. 1. The effect on pain of the combination of nalbuphine (5 mg) and naloxone (0.4 mg) plotted as changes in pain level over the 3 h following administration. Predrug pain levels are indicated to the left of the arrow at time 2 10 min.
146
B.L. Schmidt et al. / Neuroscience Letters 343 (2003) 144–146
A variety of analgesic agonists, including selective k-opioid agonists and morphine, activate an anti-analgesia system involving the putative endogenous k-opioid agonist dynorphin [3]. Similar to the human data presented here, activation of the antianalgesic actions of dynorphin is antagonized by naloxone [4]. More recent data demonstrates that the mechanism responsible for dynorphin-mediated antianalgesia involves the release of intracerebral interleukin-1b (IL-1b); in fact, dynorphin is not antianalgesic in animals genetically deficient in release of IL-1b [10]. Interestingly, while k-opioid agonists activate a centrally mediated antianalgesic mechanism that can be antagonized by naloxone [4], k-opioid agonist effectiveness with neuropathic-type pain appears to occur through a peripheral mechanism [1]. Such a combination of peripheral and central effects of nalbuphine and naloxone, respectively, might explain the reduction of neuropathic pain observed in the three cases described here. Regardless of the mechanism, the results of the current study raise the possibility of a novel treatment for chronic neuropathic pain. However, a double-blind placebo-controlled study is needed to confirm our findings in these case reports as well as an evaluation of the use of repeated administration in this patient population.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
Acknowledgements This work was supported by NIH grant NR03923.
[10]
[11]
References [1] G. Catheline, G. Guilbaud, V. Kayser, Peripheral component in the
enhanced antinociceptive effect of systemic U-69,593, a kappa-opioid receptor agonist in mononeuropathic rats, Eur. J. Pharmacol. 357 (1998) 171 –178. G. Catheline, V. Kayser, G. Guilbaud, Further evidence for a peripheral component in the enhanced antinociceptive effect of systemic morphine in mononeuropathic rats: involvement of kappa-, but not delta-opioid receptors, Eur. J. Pharmacol. 315 (1996) 135 –143. J.M. Fujimoto, K.S. Arts, J.J. Rady, L.F. Tseng, Spinal dynorphin A (1–17): possible mediator of antianalgesic action, Neuropharmacology 29 (1990) 609 –617. J.M. Fujimoto, J.J. Rady, Intracerebroventricular physostigmineinduced analgesia: enhancement by naloxone, beta-funaltrexamine and nor-binaltorphimine and antagonism by dynorphin A (1–17), J. Pharmacol. Exp. Ther. 251 (1989) 1045–1052. R.W. Gear, C. Miaskowski, N.C. Gordon, S.M. Paul, P.H. Heller, J.D. Levine, Action of naloxone on gender-dependent analgesic and antianalgesic effects of nalbuphine in humans, J. Pain 1 (2000) 122 –127. R.W. Gear, C. Miaskowski, N.C. Gordon, S.M. Paul, P.H. Heller, J.D. Levine, The kappa opioid nalbuphine produces gender- and dosedependent analgesia and antianalgesia in patients with postoperative pain, Pain 83 (1999) 339–345. J. Gregg, Non-surgical management of traumatic neuralgias and sensory neuropathies, Oral Maxillofac. Surg. Clin. N. Am. 4 (1992) 375 –392. W.S. Kingery, A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes, Pain 73 (1997) 123 –139. M.A. Pogrel, S. Thamby, Permanent nerve involvement resulting from inferior alveolar nerve blocks, J. Am. Dent. Assoc. 131 (2000) 901 –907. J.J. Rady, J.M. Fujimoto, Confluence of antianalgesic action of diverse agents through brain interleukin(1beta) in mice, J. Pharmacol. Exp. Ther. 299 (2001) 659– 665. E.M. Zola, D.C. McLeod, Comparative effects and analgesic efficacy of the agonist-antagonist opioids, Drug Intell. Clin. Pharm. 17 (1983) 411 –417.