Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine

Conno, F. De; Caraceni, Augusto; Martini, Cinzia; Spoldi, E.; Salvetti, Monica; Ventafridda, Vittorio

doi:10.1016/0304-3959(91)90225-m

Cited by 166 publications

(64 citation statements)

References 15 publications

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“…It does however produce hyperalgesia and allodynia when administered intrathecally or intracerebroventricularly (Woolf, 1981;Yaksh et al, 1986;Yaksh and Harty, 1988) and progressively higher doses can cause seizures (Smith et al, 1990;Halliday et al, 1999). These findings are consistent with the suggestion that morphine metabolites may be responsible for the development of hyperalgesia, allodynia, and myoclonus during clinical opioid therapy (De Conno et al, 1991;Sjogren et al, 1998).…”

supporting

confidence: 54%

“…It may also explain the allodynia, hyperalgesia, and myoclonus observed after administration of high-dose morphine in humans (De Conno et al, 1991;Sjogren et al, 1993Sjogren et al, , 1994Sjogren et al, , 1998Heger et al, 1999). Our observed effects may be especially relevant to palliative care situations, where heroic doses of morphine (up to 20 g/day) are required to produce analgesia in tolerant individuals (Hagen and Swanson, 1997;Sjogren et al, 1998).…”

Section: Discussionmentioning

confidence: 72%

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Morphine-3β-d-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa

Moran

Smith²

2002

J Pharmacol Exp Ther

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High doses of intrathecally applied morphine or morphine-3␤-D-glucuronide (M3G) produce allodynia and hyperalgesia. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons in transverse slices of adult rat lumbar spinal cord to compare the actions of M3G with those of the -opioid agonist, DAMGO ([D-Ala 2 ,N-Met-Phe 4 ,Gly-ol 5 ]-enkephalin), and the ORL 1 agonist, nociceptin/orphanin FQ (N/ OFQ). M3G (1-100 M) had little or no effect on evoked excitatory postsynaptic currents (EPSC) and no effect on postsynaptic membrane conductance. In contrast, 1 M DAMGO and 1 M N/OFQ reduced the amplitude of evoked EPSCs and activated an inwardly rectifying K ϩ conductance.M3G did not attenuate the effect of DAMGO or N/OFQ on evoked EPSC amplitude. However, 1 to 100 M M3G reduced the amplitude of evoked GABAergic and glycinergic inhibitory postsynaptic current (IPSC) by up to 48%. This effect was naloxone-insensitive. The evoked IPSC was also attenuated by DAMGO, but not by N/OFQ. Because M3G reduced the frequency of tetrodotoxin-insensitive miniature IPSCs and increased paired-pulse facilitation, it appeared to act presynaptically to disinhibit substantia gelatinosa neurons. This effect, which does not appear to involve -opioid or ORL 1 receptors, may contribute to the allodynia and hyperalgesia observed after intrathecal application of high doses of morphine.

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supporting

confidence: 54%

Section: Discussionmentioning

confidence: 72%

Morphine-3β-d-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa

Moran

Smith²

2002

J Pharmacol Exp Ther

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“…44). Support for this alternative hypothesis has been evidenced in vivo in animals (2,45,46) and humans (3,47,48). Thus it is thought that analgesic tolerance arises when pain facilitatory systems become sensitized or hyperactive after repeated opioid use.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice

Muscoli¹,

Cuzzocrea²,

Ndengele³

et al. 2007

J. Clin. Invest.

131

195

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Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, often because chronic opiate therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing side effects. The mechanisms leading to tolerance are poorly understood. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice was consistently associated with the appearance of several tyrosine-nitrated proteins in the dorsal horn of the spinal cord, including the mitochondrial isoform of superoxide (O 2 -) dismutase, the glutamate transporter GLT-1, and the enzyme glutamine synthase. Furthermore, antinociceptive tolerance was associated with increased formation of several proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear factor poly(ADPribose) polymerase. Inhibition of NO synthesis or removal of O 2 -blocked these biochemical changes and inhibited the development of tolerance, pointing to peroxynitrite (ONOO -), the product of the interaction between O 2 -and NO, as a signaling mediator in this setting. Indeed, coadministration of morphine with the ONOO -decomposition catalyst, Fe(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, blocked protein nitration, attenuated the observed biochemical changes, and prevented the development of tolerance in a dose-dependent manner. Collectively, these data suggest a causal role for ONOO -in pathways culminating in antinociceptive tolerance to opiates. Peroxynitrite (ONOO -) decomposition catalysts may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.

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“…These clinical uses of opiates often require opiate treatment for extended periods. A potential problem which has been noted with sustained opiate administration is the paradoxical expression of pain in regions unaffected by the initial pain complaint (Compton et al, 2001;De Conno et al, 1991;Devulder, 1997;Doverty et al, 2001;Sjogren et al, 1994). Opioid-induced 'pain', i.e.…”

Section: Introductionmentioning

confidence: 99%

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

King

Gardell

Wang

et al. 2005

Pain

153

128

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Opiates are among the most important drugs for treatment of moderate to severe pain and prolonged opiate administration is often required to treat chronic pain states. We investigated the neurobiological actions of sustained opiate administration revealing paradoxical pronociceptive adaptations associated with NK-1 receptor function. Sustained morphine delivered over 6 days elicited hyperalgesia in rats and mice during the period of opiate delivery. Sustained morphine administration increased substance P (SP) and NK-1 receptor expression in the spinal dorsal horn. Sustained morphine treatment also enhanced capsaicin-evoked SP release in vitro, and increased internalization of NK-1 receptors in response to noxious stimulation. While NK-1 receptor internalization was observed primarily in the superficial laminae of placebo-treated rats, NK-1 receptor internalization was seen in both superficial and deep lamina of the dorsal horn in morphinetreated animals. Morphine-induced hyperalgesia was reversed by spinal administration of an NK-1 receptor antagonist in rats and mice, and was observed in wildtype (NK-1 +/+ ), but not NK-1 receptor knockout (NK-1 −/− ), mice. These data support a critical role for the NK-1 receptor in the expression of sustained morphine-induced hyperalgesia. Additionally, these data indicate that sustained opiate administration induces changes reminiscent of those associated with inflammatory pain. These opiate-induced changes might produce unintended deleterious actions in the course of pain treatment in patients. Understanding of sustained morphine-induced neurochemical changes will help identify approaches that limit the deleterious actions of opiates.

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Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine

Abstract: We report the case of a patient who developed myoclonus and hyperalgesia following administration of high-dose subarachnoid morphine. This complication occurred with 40-80 mg/day continuous infusion. The pathophysiology of these side effects is discussed.

Cited by 166 publications

References 15 publications

Morphine-3β-d-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa

Morphine-3β-d-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa

Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

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