Letters. Reduction in Hyperalgesia and Intrathecal Morphine Requirements By Low-Dose Ketamine Infusion

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1 Vol. 14 No. 3 September 1997 Journal of Pain and Symptom Management 129 Letters Reduction in Hyperalgesia and Intrathecal Morphine Requirements By Low-Dose Ketamine Infusion To the Editor: We would like to report our use of a continuous low-dose intravenous infusion of the N-methyl-D-aspartate (NMDA)-receptor antagonist ketamine in a patient with pain uncontrolled by high-dose intrathecal morphine. The ketamine infusion improved analgesia, and allowed progressive reduction in daily morphine dose, with minimal opioid withdrawal effects. Case Report A 60-year-old man with a past history of severe cervical and lumbar osteoarthritis resulting in both neck and back pain presented to the Pain Management Centre for review of his intrathecal therapy. He had first experienced low back pain in Spondylolisthesis was corrected by spinal fusion at the level of the fifth lumbar and first sacral vertebra. The patient remained pain free for several years. In 1989, he developed left groin pain. Myelography revealed disc protrusion at L3/4. Local anesthetic injection of the third lumbar (L3) nerve root improved the pain, and he proceeded to L3 laminotomy. He continued to experience pain in his left leg, and following response to a temporary stimulating lead, a dorsal column stimulator was inserted in April Groin and leg pain was reduced but difficulty walking, due to pain, persisted. Later in 1992, the patient developed pain in the left arm, associated with paresthesia along the lateral aspect of the forearm, and weakness. A computerized tomographic scan and myelogram revealed generalized degenerative changes and osteophyte formation, with impingement on the sixth cervical nerve root. A laminotomy at the sixth cervical level was U.S. Cancer Pain Relief Committee, 1997 Published by Elsevier, New York, New York performed. Pain at rest and paresthesia diminished, but pain on movement and lifting with the left arm persisted. For the next 12 months, oral morphine was required for analgesia. The dose was progressively increased to 300 rag/day. High doses of oral morphine were associated with side effects of vomiting and significant sedation, making it difficult for the patient to continue working. An intrathecal infusion pump (Medtronic 8615:18 ml reservoir with side port) was implanted. Initial analgesic response was satisfactory, but the dose of morphine subsequently increased to 30 mg morphine per day and continued at this level for over 12 months. Clonidine was added to the intrathecal infusion, but with only minor improvement. On presentation, the patient described deep aching pain in the left groin and anterior thigh, and stabbing pain in the left knee. His walking tolerance was limited to 50 meters, and pain was also increased by prolonged sitting or bending. In addition, he had left sided neck pain that radiated down the lateral aspect of the arm. This was less severe than his lower limb pain, but he had difficulty lifting objects with his left hand. Hyperalgesia was present in the left leg, particularly the lateral aspect of the lower leg, and also the left arm. He experienced "pins and needles" in his left thumb and forefinger. The patient was extremely uncomfortable and had to continually change position to try and reduce his pain. The intrathecal reservoir contained morphine tartrate 53.3 mg/ml and clonidine hydrochloride 41pg/mL. The daily dose was morphine 32 mg, and clonidine 24 lag. Following admission, the intrathecal infusion was temporarily ceased, and the side port of the intrathecal pump was accessed. Cerebrospinal fluid aspirated freely, and injection of radio-opaque contrast confirmed intrathecal position of the catheter. Three milliliters of /97/$17.00

2 130 Letters Vol. 14 No. 3 September 1997 bupivacaine 0.25% was administered via the side port resulting in a sensory block to the sixth thoracic dermatome and complete relief of groin and leg pain. Three hours later, with regression of the sensory block, pain in the leg recurred. A further single dose of 1.5 ml bupivacaine 0.25% was administered intrathecally, and an intravenous infusion of ketamine was commenced at 10 mg/hr. Intrathecal morphine and clonidine infusion was recommenced, but with a 30% dose reducfon. During admission, a multidisciplinary assessment was completed and included review by a neurologist, rheumatologist, physiotherapist, orthopedic surgeon, and psychiatrist. Serum electrolytes, renal and liver function, and full blood examination were within normal limits. No abnormality was detected by lower abdominal and pelvic ultrasound. Electromyography (EMG) of the left rectus femoris, iliopsoas, and adductor magnus was normal. The EMG was directed at these muscles due to the main complaint of groin pain, but study of other muscles may have provided further information. Lumbar myelography and subsequent computerized tomography revealed left lumbar (L3/4) posterolateral disc protrusion, with the L3 nerve roots exiting normally, but minor compression of the left L4 nerve root. There was no evidence of arachnoiditis. Plain radiography of the pelvis and hips showed generalized osteoarthritis in the lumbar spine and moderate degenerative changes in both hips, but more marked in the left hip. Ketamine infusion was continued for 18 days at low-dose rates varying between 10 and 20 mg/hr ( mg/kg/hr). Satisfactory analgesia was achieved and allowed progressive reduction in intrathecal morphine dose (Figure 1). The patient experienced mild hallucinations on three occasions, which were controlled by reduction in the ketamine infusion rate for brief periods, and required oral diazepam 10 mg on ohly one occasion. Morphine withdrawal was anticipated, and additional oral clonidifie (50 tag twice daily, i increasing to 100 tag three times daily) was administered. On dayj 6, he experienced sweating and malaise, which improved after two doses of oral morphine 10 rag. As the intrathecal infusion rate decreased, the pump reservoir was refilled with a more dilute solution: morphine sulfate 8.3 mg/ml and clonidine FmMoRPH,.~ J m'd Y / 20 i ~ I --m-- KETAMINE i rng]hr ] a, DAYS Fig. 1. Intrathecal morphine and intravenous ketamine dosage. pg/ml. On day 12, the intrathecal infusion was ceased. The following day the patient was sweating and unwell, which was felt to be related to opioid withdrawal, and symptoms resolved following an intrathecal bolus of 1 mg morphine and recommencement of 2 mg/day intrathecal morphine infusion. The intravenous ketamine infusion was weaned. Left groin, leg, and arm pain remained controlled by intrathecal morphine 2 mg/day and clonidine 6 lag/day, and there was a sustained reduction in the hyperalgesia affecting the left arm and leg. The patient was discharged from hospital, 8 days after recommencement of the intrathecal infusion. A left total hip replacement has subsequently been performed with some minor improvement in left' groin pain. The patients pain has remained difficult to control adequately, but the intrathecal morphine requirement only slowly increased over the next 12 months, to a daily dose of 15 mg morphine. Comment Many factors contribute to the increasing dose requirements seen in patients receiving long-term opioids, including disease progression, reduced opioid responsiveness in some pain states, and the development of tolerance. Disease progression was evidenced by further degenerative changes in the hip requiring surgery. Technical problems of catheter dislodgment or pump malfunction must also be considered if intrathecal analgesia deteriorates, and were excluded in this case. Possible explanations for the reduced morphine requirements during and following ket-

3 Vol. 14 No. 3 September 1997 Letters 131 amine infusion in this case include an additive analgesic effect, greater efficacy of an NMDA antagonist for neuropathic pain, placebo effect due to the infusion and/or hospital admission, or reversal of opioid tolerance. Ketamine is an antagonist at the NMDA receptor in the dorsal horn, 1 and is a potent analgesic at subanesthetic doses (0.12 and 0.25 mg/kg).2 Continuous intravenous infusion of ketamine mg/hr ( mg/kg/hr) provided analgesia and improved mobility in this patient. An additive analgesic effect of the ketamine or a placebo response may have been responsible for the improved analgesia; but if these were the only factors involved, we would have expected a more rapid increase in intrathecal morphine requirements following cessation of the intravenous ketamine infusion. In chronic pain states, ongoing afferent input into the dorsal horn results in central sensitization due to NMDA receptor activation, with expansion of receptive fields, reduction in threshold, and an increase in the magnitude and duration of response to stimuli. 3'4 NMDA receptor antagonists reduce the development of central sensitization. 4 Ketamine has been shown to reduce wind-up-like pain (that is, pain evoked by repeatedly pricking the affected skin). 5 In addition to somatic pain from arthritis, this patient also described features of neuropathic pain, resulting from previous surgery and impingement on nerve roots by degenerative changes in the cervical and lumbar spine. Ketamine has been shown to reduce hyperalgesia and allodynia in patients with chronic neuropathic pain 6'7 and to have greater efficacy than placebo or morphine in the specific neuropathic pain associated with postherpetic neuralgia. 5 The analgesic response to opioids varies in different pain states, and is reduced in neuropathic pain. 5'8 The antinociceptive effects of morphine have been shown to be reduced in nerve-injured rats, 9 and patients with neuropathic pain may require higher doses of opioids. Activation of the NMDA receptor, which can lead to hyperalgesia, has been postulated as one mechanism contributing to changes in opioid responsiveness. 1 Daily treatment with the NMDA antagonist MK-801 prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose-response curve in rats. 9 Thus, a combination of NMDA antagonist and opioid may be beneficial in patients with neuropathic pain, and a long-term subcutaneous infusion of ketamine improved analgesia and reduced opioid requirements in a patient with neuropathic cancer painj 1 Multiple biochemical processes are altered when cells or animals are chronically exposed to morphine. 12 Manipulations which prevent NMDA receptor activation 9a3 or the intracellular consequences of NMDA receptor activation 14'15 have been shown to reduce the development of tolerance. NMDA receptor antagonists have also been shown to reverse morphine tolerance and prevent the withdrawal syndrome in morphine-treated rats. 1~ In the clinical setting, the development of opioid tolerance requires increased doses of opioids, and only becomes problematic if intolerable side effects supervene before analgesic levels are reached. In this patient, side effects of vomiting and sedation limited the increase in oral dosage, and the route of administration was changed from oral to intrathecal. The initial analgesic response was satisfactory, but later escalation of opioid dose was required. Eventually, pain was not controlled. Ketamine infusion re-established analgesia, which was maintained with a much reduced intrathecal dose of morphine. Thus, ketamine may have acted in part by reversing morphine tolerance. Clinical use of ketamine 'has been limited by dose-dependent psychomimetic and cardiovascular side effects. Alterations in perception, impaired performance on tests of vigilance and verbal fluency and memory, and symptoms similar to dissociative states have been shown to occur with intravenous ketamine 0.5 mg/kg over 40 min. A lower dose of ketamine 0.1 mg/kg was not significantly different from placeboj 6 In this case, continuous infusion of ketamine provided analgesia at doses ranging between 0.14 and 0.24 mg/kg/hr. Mild hallucinations were easily controlled in this patient by short-term reductions in hourly ketamine dose until side effects resolved, and by administration of oral diazepam (10 mg) on one occasion. Bolus doses of ketamine in normovolaemic patients are associated with sympathetic stimulation and increases in heart rate and blood pressure. Cardiovascular parameters were carefully monitored in this patient as he had a

4 132 Letters Vol. 14 No. 3 September 1997 past history of coronary artery disease, and intermittent angina. Blood pressure and heart rate remained stable and he experienced no episodes of chest pain. Oral clonidine premedication has been shown to reduce the cardiovascular response to anesthetic induction with ketamine. 17 Our patient received oral clonidine lag three times daily, which may have contributed to the cardiovascular stability. The hyperalgesia experienced by this patient was most likely due to neuropathic pain. However, administration of high doses of morphine via oral and parenteral routes, is and intrathecal morphine in doses from 30 to 200 mg/day, have also been associated with hyperalgesia and myoclonus. 19 This effect has been elicited in animal studies, and is not reversed by naloxone, suggesting a nonopioidreceptor mechanism. 2 Resumption of a much lower intrathecal dose of morphine may have contributed to the reduction in hyperalgesia. In conclusion, rapid reduction in intrathecal morphine dosage and hyperalgesia, was facilitated by the use of a continuous low dose intravenous ketamine infusion. Opioid withdrawal symptoms and side effects due to ketamine were minimal and easily controlled. NMDA receptor antagonists may have a role in patients who have inadequate analgesia or unacceptable side effects with high intrathecal doses of opioids. Suellen M. Walker, MB BS, FANZCA, and Michael J. Cousins, MB BS, MD, FANZCA, FRCA Pain Management and Research Centre University of Sydney Royal North Shore Hospital St. Leonard's New South Wales Australia PII S (97) References 1. Yamamura T, Harada K, Okamura A, Kemmotsu O. Is the site of action of ketamine anesthesia the N-methyl-d-aspartate receptor? Anesthesiology 1990;72: Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981;53: Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983;308: Woolf CJ, Chong MS. Pre-emptive analgesia-- treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77: Eide PK, Joum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartate receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58: Backonja M, Arndt G, Gornbar I~_, Check B, Zimmerman M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain 1994;56: Stannard CF, Porter GE. Ketamine hydrochloride in the treatment of phantom limb pain. Pain 1993;54: Portenoy RK, Foley KM, Inturissi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 1990;43: MaoJ, Price DD, Mayer DJ. Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. Pain 1995;61: Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: current view of their possible interactions. Pain 1995;62: Mercadante S, Lodi F, Sapio M, Calligara M, Serretta R. Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain. J Pain Symptom Manage 1995;10: Basbaurn AI. Insight into the development of opioid tolerance. Pain 1995;61: Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991;251: Elliot K, Minami N, Kolesnikov YA, Pasternak GW, Inturissi CE. The NMDA receptor antagonists, LY and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain 1994;56: Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995;61: KrystalJH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitve NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51: Doak GJ, Duke PC. Oral clonidine premeditation attenuates the haemodynamic effects associated with ketamine anaesthetic induction in humans. Can J Anaesth 1993;40: Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine4nduced hyperalgesia after dis-

5 Vol. 14 No. 3 September 1997 Letters 133 continuing or substituting morphine with other opioid agonists. Pain 1994;59: De Conno F, Caraceni A, Martini C, Spoldi E, Salvetti M, Ventafridda V. Hyperalgesia and myoclonus with intrathecal infusion of high dose morphine. Pain 1991;47: Yaksh TL, Harty GJ, Onofrio BM. High doses of spinal morphine produce a nonopiate receptormediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1986;64: Experience of Recurrent Abdominal Pain: Evaluation Based on the Eland Scale To the Editor: Recurrent abdominal pain (RAP) has an estimated prevalence of 10%-20% in schoolage children. 1 In addition to emotional disorders, significant organic abnormalities have also been identified in children with RAP. Despite the abundance of literature on the topic, however, there is still a great deal to be done in terms of its evaluation, diagnosis, and treatment. For about 2 years now, our department has been using the Eland scale to evaluate RAP. This pain assessment method was proposed some time ago and has been validated for use in children; it has proved capable of providing information on the amount and the site of the pain (Eland, unpublished observations, 1974). The scale is used to establish whether the pain is on the front and/or back of the body by use of a card in the shape of a human body (Figure 1), and to indicate the intensity of the pain on the basis of a color scale. For a more accurate definition of the pain site, we have experimented with the use of two grids traced on transparencies: one is placed on top of the test shape and divides the abdomen into nine anatomical quadrants (Figure 2a), and the other is placed on top of the first and further divides each square in the first grid into smaller, 0.25 cm 2 units (Figure 2b). This method enables a precise evaluation of the site and an accurate definition of the extent in cm 2 of the abdominal pain reported by the patient. In our experience, this method for analyzing the information obtained with the Eland Fig. 1. The front of shape proposed by Eland scale. Fig. 2. Left, the shape divided by first grid into nine anatomical quadrants. Right, the second grid with 0.25 cm 2 units.