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PAIN MEDICINE

Allodynia After Acute Intrathecal Morphine Administration in a Patient with Neuropathic Pain After Spinal Cord Injury

Pain Management & Research Centre, University of Sydney, Royal North Shore Hospital, Sydney, Australia

Address correspondence and reprint requests to Dr. Eric Parisod, Hôpital Universitaire de Genève, Dept d’Anesthésie, 21 rue Micheli-du-Crest, 1211 Genève 14, Switzerland. Address e-mail to eparisod{at}perso.ch

	Abstract

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IMPLICATIONS: Acute intrathecal administration of relatively small doses of opioids may precipitate neuropathic pain and allodynia in those with spinal cord injury.

	Introduction

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A number of case reports have described allodynia, hyperalgesia, and myoclonus after the administration of morphine (1–7). Similar behavioral features have also been observed in animals (8–12). However, these phenomena were mostly observed after large doses or long-term administration of morphine. Thus, the mechanisms suggested to explain this phenomenon have generally been dependent on the consequences of a large spinal concentration of morphine and the effects of morphine metabolite accumulation after long-term administration. In this report, we present a case in which a single, relatively small dose of intrathecal morphine induced allodynia twice in the dermatomes close to the level of injury in a patient with spinal cord injury (SCI).

	Case Report

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The patient was a 66-yr-old man with a T8 complete paraplegia after an accident 12 yr previously, when he was struck by a tree limb while removing it with a chain saw. During the first year after the accident, the patient experienced some at-level neuropathic SCI pain (13) in the T6 and T7 dermatomes, mostly on the right side. He described the pain as sharp, shooting, cramping, and burning. The pain was spontaneous and intermittent and was increased by movement and touch. This pain had resolved, and it recurred only once, for a day, for no apparent reason, 2 yr previously.

At the time of presentation, the patient mostly had below-level neuropathic SCI pain (13), perceived within the abdomen, in both groins and testicles and spreading down the inside of both legs. The abdominal pain was the most distressing and was described as cramping and burning in nature, with some paroxysmal spasms during which he had to stop working. It worsened with fatigue or stress, during heavy activity, and during bladder infections. The pain below the groin was milder and was present continuously, although it fluctuated in severity. He also reported some burning sensation over both feet.

The patient had undergone a number of procedures in an attempt to relieve his below-level neuropathic pain. He had a T7-10 laminectomy 2 yr after his injury to remove a bone fragment protruding into the spinal canal. He obtained some improvement (60% reduction of the pain), but unfortunately this lasted only 8 wk. He obtained some short-term pain relief from an IV lignocaine injection but did not obtain any benefit from repeated right intrathoracic splanchnic blocks. Three years after his injury, a dorsal root entry zone procedure at T7 gave him complete relief of his abdominal pain, but the relief lasted only 6 mo. He obtained no benefit from a lumbar sympathetic block or from transcutaneous electrical nerve stimulation applied on his back at the level of the cord lesion. Nine years after his injury, an intrathecal fentanyl injection (30 µg) at T3-4 was unsuccessful and caused significant thoracic pruritus. Cognitive interventions using relaxation with imagery and deep breathing were also ineffective in relieving his pain. Involvement in work remained the most effective pain-reduction strategy. He also tried a number of medications, including clonazepam, valproic acid, carbamazepine, gabapentin, mexiletine, amitriptyline, doxepin, oral clonidine, and paracetamol with dextropropoxyphene. None of these produced substantial sustained benefit, and many produced significant side effects.

The patient was admitted for a trial of morphine and clonidine administered intrathecally. He received three intrathecal bolus injections at the lumbar level. Morphine, clonidine, and then normal saline were administered at intervals of 24 h without affecting the pain. He had no major side effect apart from some drowsiness after the normal saline injection. The hemodynamic and respiratory variables remained stable. An intrathecal injection of 3 mL of contrast (Isoview 300) showed an interruption of the spread of the contrast at T10, where the T9 crushed vertebra was obliterating the spinal canal. Intrathecal testing was then continued through a catheter placed above the level of SCI under radiograph control at approximately T4.

On the first day, the patient received a 50-µg clonidine bolus, followed by a continuous infusion of 50 µg/h for 9 h. This did not affect the pain. The patient complained of subjective dry mouth and drowsiness and exhibited some mild subclinical hypotension and bradycardia. On the second day, the patient received a 0.5-mg morphine bolus. This failed to produce any pain relief but, rather, induced mechanical allodynia 2 h after administration in a band over the T6 and T7 dermatomes on the right side, which faded overnight but was still present 24 h after the injection. The allodynia was reported as a painful sensation after light touch with clothes or sheets. It was present in the same distribution as the at-level neuropathic pain experienced during the first year after injury. There were no major hemodynamic or respiratory side effects, but he complained of some drowsiness, nystagmus, blurred vision, and severe pruritus half an hour after the injection, for which he required a continuous infusion of naloxone 50 µg/h during the night. This relieved the pruritus but did not affect the allodynia.

On the third day, the patient received 100 mg of lignocaine intrathecally, which markedly reduced (>50%) the remaining allodynia for 90 min before the allodynia recurred, but it did not relieve the abdominal pain. We then administered clonidine (20-µg bolus) followed by a continuous infusion of clonidine (20 µg/h). This regimen did not affect his abdominal pain. The allodynia subsided 5 h after the administration of clonidine and was believed to have abated spontaneously rather than as a result of the clonidine. The side effects on this day seemed to be related to the administration of clonidine, with a mild decrease of blood pressure and mild sedation.

On the last day, the patient received an intrathecal injection containing 0.2 mg of morphine and 25 µg of clonidine. This again failed to affect his usual abdominal pain but triggered, for an hour and a half, the recurrence of allodynia at the level of the injury. The patient was then believed to be unsuitable for intrathecal morphine therapy and was discharged on his usual regimen of oral paracetamol and dextropropoxyphene.

	Discussion

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The onset of "paradoxical pain"—allodynia, hyperalgesia, and myoclonus—after the administration of opioids has been described previously (1–4,7,14). These features can occur with various routes of administration and at different dose levels, although large doses seem to facilitate the onset of the syndrome (1–4,7). This is the first case report of increased neuropathic pain and allodynia after acute administration of a small dose of intrathecal morphine.

The mechanisms responsible for the onset of allodynia, hyperalgesia, and myoclonus after morphine administration are not clear. It has been suggested that hyperalgesia may be due to opioid "miniwithdrawals," which occur between intermittent opioid administration (15). This mechanism is dependent on intermittent removal of the inhibitory effect of opioids but does not seem to apply to this case, in which allodynia was induced by acute administration on two separate occasions.

Another suggested mechanism is a direct excitatory effect (16) of opioids on either N-methyl-D-aspartate receptor-mediated responses (17) or other non-opioid receptors (2–4,6). Most case reports have demonstrated that the allodynia/hyperalgesia syndrome disappeared when the morphine was reduced or discontinued and replaced by another opioid such as methadone (3,4,6) and that symptoms were often not reversed with opioid receptor antagonists (8,9,18).

Another suggested mechanism for the production of hyperalgesia is the effect of morphine metabolites. M3G is devoid of analgesic activity and produces hyperalgesia and allodynia in rats when it is administered by both intrathecal (9,12,16,19) and intracerebroventricular (8,20) routes. In addition, some authors have demonstrated that M3G is a potent antagonist of the analgesic effect of morphine or, more specifically, M6G (8,12,20,21). A report of morphine-induced allodynia in a child with a brain tumor correlated the occurrence of allodynia with a large blood level of M3G and the ratio of M3G to morphine, rather than to the blood level of morphine itself (6). However, the rapid onset of symptoms after administration in our case appears to preclude metabolite formation as an explanation.

An excitatory effect of opioids may be due to interference with normal spinal inhibitory processes mediated by -aminobutyric acid (GABA) and glycine (22–24). Spinal administration of strychnine, which affects glycinergic transmission, administered in submotor convulsive doses, produces a behavioral phenomenon that is comparable to morphine-induced allodynia (11,25). It has been postulated that large doses of opioids antagonize postsynaptic GABA- and glycine-mediated inhibition, causing hyperalgesia and myoclonus (1,9,10,16,26). Morphine or its metabolites may also result in the disinhibition of GABAergic control systems on low-threshold afferents converging on nociceptive neurons at the level of spinal cord (10,18).

The mechanisms outlined previously have all been proposed as mechanisms for the development of allodynia, hyperalgesia, and myoclonus after morphine administration. However, most fail to explain the allodynia observed in this case report. Many of the previous cases may have been due to direct excitation or disinhibition after the administration of large doses or an effect of metabolite accumulation after long-term administration. However, in this study, the patient reported allodynia immediately after intrathecal administration of a relatively small dose of morphine. This case, therefore, helps to shed further light on the mechanisms of morphine-induced allodynia, as well as on understanding the mechanisms that may underlie allodynia after SCI in several ways.

The repeated relationship between morphine administration and the onset of allodynia in this case illustrates well the involvement of morphine in the onset of symptoms. Although a small dose of morphine was administered, altered cerebrospinal (CSF) flow may have resulted in a very large drug concentration of intrathecally administered drugs in the CSF caudal to the site of damage (12,27). However, in this case, intrathecal administration below the level of injury resulted in neither pain relief nor allodynia. Allodynia occurred only with administration above the level of injury, where, presumably, there is no obstruction of rostral flow of CSF and there is free distribution of the drug. Therefore, it seems unlikely that large concentrations of morphine were responsible for local excitation resulting in allodynia.

The distribution of allodynia in the dermatomes in which the patient had experienced pain previously suggests another mechanism. The changes that occur after intrathecal administration of morphine appear to occur at a spinal level. In animal models (12) and cancer patients (2), the administration of large doses of intrathecal morphine produces a segmental hyperalgesia and allodynia. This suggests that there may be an underlying functional abnormality at these segmental spinal levels. Animal studies of pain after SCI appear to indicate that there are changes in GABAergic and glycinergic function close to the site of injury (28,29) that may result in a segmental allodynia similar to that experienced by the patient in this study (30,31). Therefore, it could be hypothesized that the patient had an underlying dysfunction of GABAergic and/or glycinergic inhibition that was sufficient to cause allodynia at one point after his injury. However, other processes may have acted to compensate so that allodynia was no longer experienced. As mentioned previously, it has been proposed that spinally administered morphine may affect inhibition (10). In the presence of an underlying minor disturbance, even relatively small doses of opioids may be sufficient to cause further GABAergic and glycinergic dysfunction (10) and to trigger the allodynia.

Thus, this case provides further support for the hypothesis that the allodynia and hyperalgesia observed in some cases after the administration of morphine are due to interference with normal inhibitory processes. This may overlap with the interference of inhibition that occurs in some people with SCI which makes them more susceptible to the induction of morphine-induced allodynia. Our experience indicates that effective relief in this situation does not occur with opioid antagonism with naloxone but does occur with spinal administration of a local anesthetic.

	References

Top Abstract Introduction Case Report Discussion References

 

1. Potter JM, Reid DB, Shaw RJ, et al. Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. BMJ 1989; 299: 150–3.
2. Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology 1990; 72: 743–5.[Web of Science][Medline]
3. Sjogren P, Jonsson T, Jensen N-H, et al. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993; 55: 93–7.[Web of Science][Medline]
4. Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain 1994; 59: 313–6.[Web of Science][Medline]
5. Bowsher D. Paradoxical pain. BMJ 1993; 306: 473–4.
6. Heger S, Maier C, Otter K, et al. Morphine induced allodynia in a child with brain tumour. BMJ 1999; 319: 627–9.[Free Full Text]
7. De Conno F, Caraceni A, Martini C, et al. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain 1991; 47: 337–9.[Web of Science][Medline]
8. Labella FS, Pinsky C, Havlicek V. Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity. Brain Res 1979; 174: 263–71.[Web of Science][Medline]
9. Woolf CJ. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res 1981; 209: 491–5.[Web of Science][Medline]
10. Werz MA, Macdonald RL. Opiate alkaloids antagonize postsynaptic glycine and GABA responses: correlation with convulsant action. Brain Res 1982; 236: 107–19.[Web of Science][Medline]
11. Beyer C, Roberts LA, Komisaruk BR. Hyperalgesia induced by altered glycinergic activity at the spinal cord. Life Sci 1985; 37: 875–82.[Web of Science][Medline]
12. Yaksh TL, Harty GJ. Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Exp Ther 1988; 244: 501–7.[Abstract/Free Full Text]
13. Siddall PJ, Taylor DA, Cousins MJ. Classification of pain following spinal cord injury. Spinal Cord 1997; 35: 69–75.[Web of Science][Medline]
14. Morley JS, Miles JB, Wells JC, Bowsher D. Paradoxical pain. Lancet 1992; 340: 1045.[Web of Science][Medline]
15. Gutstein HB. The effects of pain on opioid tolerance: how do we resolve the controversy? Pharmacol Rev 1996; 48: 403–7.[Web of Science][Medline]
16. Crain SM, Shen KF. Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol Sci 1990; 11: 77–81.[Medline]
17. Chen L, Huang LY. Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron 1991; 7: 319–26.[Web of Science][Medline]
18. Yaksh TL, Harty GJ, Onofrio BM. High doses of spinal morphine produce a nonopiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1986; 64: 590–7.[Web of Science][Medline]
19. Smith GD, Smith MT. Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat. Pain 1995; 62: 51–60.[Web of Science][Medline]
20. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990; 47: 579–85.[Web of Science][Medline]
21. Gong QL, Hedner J, Bjorkman R, Hedner T. Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 1992; 48: 249–55.[Web of Science][Medline]
22. Dickenson AH. Mechanisms of the analgesic actions of opiates and opioids. Br Med Bull 1991; 47: 690–702.[Abstract/Free Full Text]
23. Sawynok J. GABAergic mechanisms of analgesia: an update. Pharmacol Biochem Behav 1987; 26: 463–74.[Web of Science][Medline]
24. Game CJA, Lodge D. The pharmacology of the inhibition of dorsal horn neurones by impulses in myelinated cutaneous afferents in the cat. Exp Brain Res 1975; 23: 75–84.[Web of Science][Medline]
25. Sherman SE, Loomis CW. Morphine insensitive allodynia is produced by intrathecal strychnine in the lightly anesthetized rat. Pain 1994; 56: 17–29.[Web of Science][Medline]
26. Curtis DR, Duggan AW. The depression of spinal inhibition by morphine. Agents Actions 1969; 1: 14–9.[Medline]
27. Siddall PJ, Molloy AR, Walker S, et al. Efficacy of intrathecal morphine and clonidine in the treatment of neuropathic pain following spinal cord injury. Anesth Analg 2000; 91: 1493–8.[Abstract/Free Full Text]
28. Davidoff RA, Graham LT, Shank RP, et al. Changes in amino acid concentrations associated with loss of spinal interneurons. J Neurochem 1967; 14: 1025–31.[Web of Science][Medline]
29. Demediuk P, Daly MP, Faden AI. Effect of impact trauma on neurotransmitter and nonneurotransmitter amino acids in rat spinal cord. J Neurochem 1989; 52: 1529–36.[Web of Science][Medline]
30. Hao JX, Xu XJ, Yu YX, et al. Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischaemia: implications for a tonic GABAergic inhibitory control of myelinated fiber input. J Neurophysiol 1992; 68: 392–6.[Abstract/Free Full Text]
31. Zhang AL, Hao JX, Seiger A, et al. Decreased GABA immunoreactivity in spinal cord dorsal horn neurons after transient spinal cord ischaemia in the rat. Brain Res 1994; 656: 187–90.[Web of Science][Medline]

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