Grande, Lucinda A. MD*; O’Donnell, Brendan R. MD*; Fitzgibbon, Dermot R. MD*; Terman, Gregory W. MD, PhD*†
The development of opioid tolerance poses a significant therapeutic challenge in both chronic and postoperative pain management. Long-term use of opioids may result in opioid escalation to achieve adequate pain relief. The occurrence of side effects such as sedation can become problematic.1 Opioid escalation can sometimes appear futile, with inadequate pain control despite very high doses. In addition, some types of pain, particularly central neuropathic pain, can be refractory to opioid therapy.2
Use of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine for pain refractory to high-dose opioids is well described in a number of clinical trials.3,4 Such use is supported by preclinical data demonstrating an important role for the NMDA receptor in opioid-induced hyperalgesia5,6 and in persistent pain from inflammation,7 nerve injury,8 and cancer.9
Widespread use of ketamine has been limited by clinicians’ concerns about adverse effects such as dysphoria, hallucinations, and dissociative symptoms. Furthermore, the dosing of ketamine is inconvenient in chronic pain patients as it is relatively short acting and is unavailable as oral tablets. Analgesic use of dextromethorphan, an oral NMDA receptor antagonist with preclinical effectiveness,10 has been largely disappointing clinically.11
Memantine is a long-acting oral NMDA receptor antagonist with a high therapeutic index.12 Its demonstrated analgesic effectiveness for neuropathic pain in case series,13,14 but not placebo-controlled trials,15–18 indicates a need to elucidate characteristics of the pain that best responds to its use.
We describe the use of ketamine and, subsequently, memantine in managing intractable pain in a setting of severe opioid tolerance.
A 43-yr-old man with known metastatic liposarcoma of the thigh presented acutely with progressive bilateral lower extremity weakness and paresthesias and with worsening of his chronic back pain. The liposarcoma had progressed over 4 yr despite multiple surgical excisions, chemotherapy, and radiation, and he had known vertebral, epidural, and pulmonary metastases. His back pain was not controlled at home despite oral methadone (120 mg/d), gabapentin (1800 mg/d), and IV hydromorphone patient-controlled analgesia (demand dose 1.2 mg, lockout period 6 min, basal rate 1.2 mg/h, total use approximately 7 mg/h).
The patient was admitted for pain management and further workup. Magnetic resonance imaging of the spine showed extension of epidural metastases with circumferential compression of the spinal cord at the T9–10 level (Fig. 1). An urgent palliative decompressive laminectomy was performed, with partial tumor resection at levels T8–L1. Improved motor function was observed in the immediate postoperative period.
Postoperatively, he reported severe burning low back and bilateral lower extremity pain of intensity rating 8–9 of 10, and a less severe stabbing upper back pain exacerbated by movement. Pain was uncontrolled despite continuation of oral methadone and gabapentin, initiation of IV lorazepam and ketorolac (90 mg/d) and escalating doses of IV hydromorphone. Hydromorphone was titrated to an average use of 63 mg/h on postoperative day (POD) 0 and reached a peak of 333 mg/h in the afternoon of POD 1 (Fig. 2), including bolus doses of up to 50 mg which had little impact on pain severity.
Because of unsatisfactory pain relief, a continuous infusion of ketamine at 55 μg kg−1 h−1 (5 mg/h) was begun on the afternoon of POD 1. After 5 h, the constant burning low back and lower extremity pains were essentially resolved and, although upper back pain continued, its intensity was tolerable at 2 of 10. During this time, his patient-controlled analgesia use decreased to about one demand dose per hour, so a downward titration of the hydromorphone infusion was begun. Over the following days, pain intensity remained at 1–3 of 10 despite a decrease in average hydromorphone use to 63 mg/h on POD 2 and 21 mg/h on POD 4 (Fig. 2). Mild somnolence which had begun with the ketamine infusion subsequently resolved with the decrease in hydromorphone use. The patient denied significant side effects such as dysphoria, hallucinations, or memory issues.
Oral memantine was started at 5 mg bid on POD 5 and ketamine was titrated downward to 27.5 μg kg−1 h−1, and then to 13.8 μg kg−1 h−1 on POD 6. This attempted ketamine taper was unsuccessful, resulting in an increase in pain intensity and hydromorphone use, both of which returned to baseline with resumption of ketamine to 55 μg kg−1 h−1 on POD 7 (Fig. 2). Also on POD 7, the memantine dose was doubled to 10 mg bid and gabapentin was increased from 1500 to 2100 mg/d.
A successful slower ketamine taper was initiated on POD 8 with a dose decrease to 36.8 μg kg−1 h−1 and discontinuation finally on POD 11. The patient reported satisfactory pain control (average intensity 1–3 of 10), and IV hydromorphone was tapered and finally discontinued on POD 13. Oxycodone 30 mg was then provided as needed, about once daily. Memantine (10 mg bid), methadone (120 mg/d), and gabapentin (2100 mg/d) were continued unchanged, and ketorolac was replaced with naproxen (1000 mg/d).
The patient’s pain remained well controlled despite a medically complicated course and progressive development of paraplegia. He was discharged to a nursing home on POD 49. On discharge, the memantine was inadvertently discontinued. During the following 2 wk he complained of a return of his burning low back pain and lower extremity pain, which proved refractory to IV morphine even when administered to the point of over sedation.
After readmission on POD 65 for pain control, he was restarted on memantine at 10 mg bid. In addition, methadone was increased in stages from 120 to 200 mg/d, and naproxen was increased from 1000 to 1500 mg/d. Over 3–4 days the pain resolved, and IV morphine was replaced with as-needed oxycodone (about 20 mg/d). After a week, he was discharged to the nursing home. He remained comfortable, alert, and lucid without further changes in analgesic regimen until his death 2 mo later from complications of pulmonary metastases (POD 112).
At least four factors contributed to this patient’s severe back and leg pain after surgery: 1) tumor, 2) spinal cord injury, 3) opioid tolerance with associated hyperalgesia, and 4) surgical trauma. The rapid and almost complete resolution of pain with an extremely low dose infusion of IV ketamine and the absence of side effects indicate a highly sensitive response to this drug. Continued pain relief with transition to memantine, loss of pain relief with its discontinuation, and return of pain relief after its resumption (and after an increase in methadone, also with NMDA receptor antagonist effects19) demonstrated that his pain was responsive to diverse NMDA receptor antagonists. The patient’s continued sharp upper back pain with movement suggests a fifth (perhaps acute musculoskeletal) pain less responsive to NMDA receptor antagonists.
Although ketamine reduces postoperative opioid requirements,20,21 its benefits have been modest in most studies. Why was this patient’s pain so opioid-resistant, yet so sensitive to NMDA receptor antagonists? We propose that sensitization of central pain pathways due to spinal cord injury, tumor, and chronic high-dose opioid use contributed to the patient’s pain, and also predisposed him to the extreme opioid tolerance evident after surgical trauma. NMDA receptor antagonists, we hypothesize, dampened central sensitization from all of these causes and this modified the mechanisms primarily responsible for his intractable pain.
Activation of the NMDA-type ionotropic glutamate receptor occurs after an intense or repeated stimulus, and results in a long-term increase in cell excitability because of second messenger effects initiated by calcium influx.22 NMDA receptors are densely expressed at nociceptive synapses in the spinal cord dorsal horn.23 A NMDA receptor-mediated increase in dorsal horn synaptic efficacy is an important contributor to the sensitization of central pain pathways seen in both chronic pain syndromes and opioid tolerance.7–9,22,24
Our patient’s spinal cord injury likely contributed to a central neuropathic pain responsive to NMDA receptor antagonists. For example, in a rat model of spinal cord injury pain, enhanced responsiveness was found in spinal sensory neurons adjacent to the lesion.25 Pain behaviors were reversed in this model by administration of an NMDA receptor antagonist.26
This patient’s tumor also likely contributed to his severe pain, not only from tissue destruction from his metastases but perhaps also from tumor-induced sensitization of nociceptive processes through a NMDA receptor-mediated mechanism. In a murine bone cancer model, for example, an increase in dynorphin immunoreactive neurons and massive astrocyte hypertrophy were demonstrated throughout the ipsilateral spinal gray matter at the level innervating the tumor27; both findings have been associated with NMDA receptor-mediated central sensitization.28–30
Finally, the patient’s profound opioid tolerance was clearly a major impediment to treating his pain successfully. Although such tolerance is likely due in part to desensitization of the opioid receptors,31 hyperalgesia, due to an opioid-induced feedback amplification of the nociceptive signal, likely also contributes.22,32 Multiple mechanisms have been reported to explain such amplification including an increase in spinal dynorphin content,33 increased astrocyte activity,34 and intracellular activation of protein kinase C6; all may act directly or indirectly via NMDA receptor activation.35–37
After chronic opioid exposure in rats, nociceptive sensitization mechanisms dependent on the NMDA receptor are in equilibrium5 with compensatory endogenous analgesic processes.38 In our patient, such opioid-induced sensitization presumably exacerbated disease-induced sensitization, and balance was maintained only by chronic high-dose opioid use. Balance was lost when tissue damage from disease progression and surgical trauma39,40 caused significant new pain. Postoperative opioid escalation appeared futile, although perhaps adequate analgesia would have been achievable with yet higher opioid doses.
However, this opioid escalation may have been truly futile. After chronic opioid exposure, additional opioid exposure leads to increasingly marked and prolonged hyperalgesia.5 Eventually, the hyperalgesia which increases over time could exceed the maximum analgesic effect which can be produced by available opiate receptors, making this pain truly refractory to opioids.
Ketamine and memantine, in this patient, may have produced their dramatic analgesic effects both by dampening the central sensitization caused by his multiple spinal pathologies and, at the same time, by diminishing the opioid-induced hyperalgesia which masked the effects of endogenous and exogenous analgesics.
This case illustrates the potential of a novel use of memantine, an uncompetitive antagonist at the NMDA-type glutamate receptor approved for clinical use in Alzheimer’s disease. Memantine’s tolerability is due to its low affinity to the receptor-associated ion channel which results in reduced dwell-time in the channel, with preferential blockade of pathologically overactivated channels.12 It is therefore a promising treatment for disorders in which the pathology includes excessive glutamate release. Examples are neurodegenerative dementias involving excitotoxic cell death12 and pain involving central sensitization such as neuropathic pain13,14 and, we suggest, opioid-induced hyperalgesia. Adverse effects of memantine such as dizziness and restlessness are mild and reversible with discontinuation.
Understanding the mechanisms interfered with by NMDA receptor antagonists may be helpful for clinicians considering the use of these drugs as analgesics. Our experience suggests that pain caused by multiple coexisting dorsal horn pathologies mediated by central sensitization can be extremely responsive to these drugs and, in particular, in the setting of severe opioid tolerance. Memantine is an additional tool for clinicians to consider when treating such complex pains. Additional controlled studies with this drug will be helpful to further guide our management.
1. Rapp SE, Ready LB, Nessly ML. Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review. Pain 1995;61:195–201
2. Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D. Effects of IV morphine in central pain: a randomized placebo-controlled study. Neurology 2002;58:554–63
3. Yang CY, Wong CS, Chang JY, Ho ST. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996;43:379–83
4. Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 2000;20:246–52
5. Celerier E, Laulin JP, Corcuff JB, Le Moal, M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci 2001;21:4074–80
6. Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995;61:365–74
7. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on NMDA receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293–9
8. Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve: excitatory amino acid antagonists. Pain 1992;49:121–8
9. Saito O, Aoe T, Kozikowski A, Sarva J, Neale JH, Yamamoto T. Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain. Can J Anaesth 2006;53: 891–8
10. Hao JX, Xu XJ. Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered excitatory amino acid receptor antagonists. Pain 1996;66:279–85
11. Galer BS, Lee D, Ma T, Nagle B, Schlagheck TG. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain 2005;115:284–95
12. Lipton SA. Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J Alzheimers Dis 2004;6:S61–S74
13. Schley M, Topfner S, Wiech K, Schaller HE, Konrad CJ, Schmelz M, Birbaumer N. Continuous brachial plexus blockade in combination with the NMDA receptor antagonist memantine prevents phantom pain in acute traumatic upper limb amputees. Eur J Pain 2007;11:299–308
14. Sinis N, Birbaumer N, Gustin S, Schwarz A, Bredanger S, Becker ST, Unertl K, Schaller HE, Haerle M. Memantine treatment of complex regional pain syndrome: a preliminary report of six cases. Clin J Pain 2007;23:237–43
15. Eisenberg E, Kleiser A, Dortort A, Haim T, Yarnitsky D. The NMDA (N-methyl-d-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study. Eur J Pain 1998;2:321–7
16. Maier C, Dertwinkel R, Mansourian N, Hosbach I, Schwenkreis P, Senne I, Skipka G, Zenz M, Tegenthoff M. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain—results of a randomized double-blinded, placebo-controlled trial. Pain 2003;103:277–83
17. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-d-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg 2000;91:960–6
18. Wiech K, Kiefer RT, Töpfner S, Preissl H, Braun C, Unertl K, Flor H, Birbaumer N. A placebo-controlled randomized crossover trial of the N-methyl-d-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004;98:408–13
19. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-d-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 1999;289:1048–53
20. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999;82:111–25
21. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004;99:482–95
22. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–74
23. Zeng J, Thomson LM, Aicher SA, Terman GW. Primary afferent NMDA receptors increase dorsal horn excitation and mediate opiate tolerance in neonatal rats. J Neurosci 2006;26:12033–42
24. Guntz E, Dumont H, Roussel C, Gall D, Dufrasne F, Cuvelier L, Blum D, Schiffmann SN, Sosnowski M. Effects of remifentanil on N-methyl-d-aspartate receptor: an electrophysiologic study in rat spinal cord. Anesthesiology 2005;102:1235–41
25. Yezierski RP, Park SH. The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat. Neurosci Lett 1993;157:115–19
26. Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF, Nguyen HO, Grocholski BM, Shoeman DW, Kehl LJ, Regunathan S, Reis DJ, Yezierski RP, Wilcox GL. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci USA 2000;97:10584–9
27. Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MC, Clohisy DR, Mantyh PW. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000;98:585–98
28. Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 2005; 28:661–9
29. Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952: 7–14
30. Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, Berman BM, Lao L. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 2008;135:232–9
31. Terman GW, Jin W, Cheong YP, Lowe J, Caron MG, Lefkowitz RJ, Chavkin C. G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal. Br J Pharmacol 2004;141:55–64
32. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87
33. Gardell LR, Wang R, Burgess SE, Ossipov MH, Vanderah TW, Malan TP Jr, Lai J, Porreca F. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002;22:6747–55
34. Song P, Zhao ZO. The involvement of glial cells in the development of morphine tolerance. Neurosci Res 2001;39: 281–6
35. Laughlin TM, Vanderah TW, Lashbrook J, Nichols ML, Ossipov M, Porreca F, Wilcox GL. Spinally administered dynorphin A produces long-lasting allodynia: involvement of NMDA but not opioid receptors. Pain 1997;72:253–60
36. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14:2301–12
37. Johnston IN, Westbrook RF. Inhibition of morphine analgesia by LPS: role of opioid and NMDA receptors and spinal glia. Behav Brain Res 2005;156:75–83
38. Thomson LS, Zeng J, Terman GW. Increased endocannabinoid inhibition in the morphine-tolerant neonatal spinal cord slice. Soc Neurosci Abstr 2006;643.9/R13
39. Kawamata M, Watanabe H, Nishikawa K, Takahashi T, Kozuka Y, Kawamata T, Omote Namiki. Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. Anesthesiology 2002;97:550–9
40. Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-d-aspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 1998;88:143–56