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Ultralow dose fentanyl prevents development of chronic neuropathic pain in rats

Elzbieta P. Wala, PhD, Joseph R. Holtman Jr, MD, PhD, Paul A. Sloan, MD


Background: Opioids may cause progressive enhancement of pain sensitivity (opioid-induced hyperalgesia [OIH]) and thus, exacerbate existing pain. Animal studies also demonstrate paradoxical OIH with an ultralow dose (ULD, subanalgesic) of opioid; eg, the µ-opioid, morphine. Repeated administration of ULD-morphine resulted in tolerance to ULD-OIH. Prior exposure to ULD-morphine prolonged subsequent morphine antinociception in intact rats (delay of tolerance) and blocked neuropathic pain in nerve-injured rats (no hyperalgesia). Hence, pre-emptive desensitization of the excitatory function of opioid receptors may reduce further activation of a pain facilitatory system exerted by opioid or nerve injury. Objective: We determined if ULD-fentanyl (µ-opioid) and U50488H (?-opioid) also affect post-nerve-injury neuropathy (a rat model of chronic constriction nerve injury [CCI]). Design: Fentanyl (0.5-500 ng/kg) was administered acutely in noninjured rats. Chronic fentanyl (5 ng/kg/day) was initiated either immediately after CCI (day 1-28) or when neuropathy was established (day 7-14) in nerve-injured rats. U50488H (25 µg/kg/day) was given on day 1-28 post-CCI. Saline served as control. Responsiveness was assessed using tail-flick and paw-pressure tests, respectively, in intact and CCI Sprague-Dawley rats of both sexes. Results: ULD-fentanyl evoked pain sensitization in noninjured rats. ULD-OIH was related to dose (inversely), gender (female > male), and was reversed by ketamine. Neuropathy developed after CCI in control (saline) rats. This was not observed in rats of either sex exposed to ULD-fentanyl on day 1-28 post-CCI. Rats treated with ULD-fentanyl from day 7 after CCI exhibited hyperalgesia similar to control rats. U50488H did not block post-CCI neuropathy (regardless of gender). Conclusions: Pre-emptive use of ULD µ-opioid (not ?-opiod) blocked initiation (not maintenance) of neuropathic pain after CCI in rats. These data may suggest a novel treatment approach in situations when the potential development of neuropathy can be anticipated. Keywords: neuropathy, opioid-induced hyperalgesia, µ-opioid agonist, ?-opioid agonist, subanalgesic dose, neuropathy initiation, neuropathy maintenance

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Sloan PA: Oxymorphone in the management of pain. Ther

Clin Risk Manag. 2008; 4: 1-11.

Sloan PA: Tapentadol for acute and chronic pain. Expert

Opinion Pharmacother. 2010; 11: 1783-1785.

Ballantine JC: Opioids for chronic nonterminal pain. South

Med J. 2006; 99: 1245-1255.

Eisenberg E, McNicol E, Carr DR: Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. JAMA. 2005; 393: 3043-3052.

Martin TJ, Eisenach JS: Pharmacology of opioid and nonopioid analgesics in chronic pain state. J Pharmacol Exp Ther. 2001; 299: 811-817.

Rosenblum A, Marsch LA, Herman J, et al.: Opioids and the

treatment of chronic pain: Controversies, current status, and

future directions. Exp Clin Psychopharmacol. 2008; 16: 405-416.

Angst MS, Clark D: Opioid-induced hyperalgesia.

Anesthesiology. 2006; 104: 570-587.

Chu LF, Angst MS, Clark D: Opioid-induced hyperalgesia in

humans. Molecular mechanisms and clinical considerations.

Clin J Pain. 2008; 24: 479-496.

Fishbain DA, Cole B, Lewis JE, et al.: Do opioids induce

hyperalgesia in humans? An evidence-based structured review. Pain Med. 2009; 10: 829-839.

Grider JS, Ackerman WE: Opioid-induced hyperalgesia and

tolerance: Understanding opioid side effects. Expert Rev Clin

Pharmacol. 2008; 1: 291-297.

Lee M, Silverman S, Hansen H, et al.: A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011; 14: 145-161.

Mao J: Opioid-induced abnormal pain sensitivity:

Implications in clinical therapy. Pain. 2002; 100: 213-217.

Mao J: Opioid-induced abnormal pain. Curr Pain Headache

Rep. 2006; 10: 67-70.

Ossipov MH, Lai J, King T, et al.: Underlying mechanism of

pronoceptive consequences of prolonged morphine exposure.

Biopolymers. 2005; 80: 319-324.

Ruscheweyh R, Sandkuhler J: Opioids and central sensitization: II. Induction and reversal of hyperalgesia. Eur J Pain. 2005; 9: 149-152.

Sandkuhler J, Ruscheweyh R: Opioids and central sensitization: I. Pre-emptive analgesia. Eur J Pain. 2005; 9: 145-148.

Silverman SM: Opioid induced hyperalgesia: Clinical implications for the pain practitioner. Pain Physician. 2009; 12: 679-684.

Simonnet G: Opioids: From analgesia to anti-hyperalgesia.

Pain. 2005; 118: 8-9.

Simonnet G, Rivat C: Opioid-induced hyperalgesia:

Abnormal or normal pain. NeuroRepor. 2003; 14: 1-7.

Wu KM, Martin WR, Kamerling SG, et al.: Possible medullary k hyperalgesic mechanism. I. A new potential role for endogenous opioid peptides in pain perception. Life Sci. 1983; 33: 1831-1838.

Kamerling SG, Martin WR, Wu KM, et al.: Medullary k hyperalgesic mechanisms. II. The effects of ethylketazocine administered into the fourth cerebral ventricle of the conscious dog. Life Sci. 1983; 33: 1839-1843.

Hamann SR, Martin WR: Opioid and nicotinic analgesic and

hyperalgesic loci in the rat brain stem. J Pharmacol Ther. 1992; 261: 707-715.

Parvini S, Hamann SR, Martin WR: Pharmacologic characteristics of a medullary hyperalgesic center. J Pharmacol Exp Ther. 1993; 265: 286-293.

Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interaction. Pain. 1995; 62; 259-274.

Angst MS, Koppert W, Pahl I, et al.: Short-term infusion of

the mu-opiod agonist remifentanyl in humas causes hyperalgesia during withdrawal. Pain. 2003; 106: 49-57.

Joly V, Richebe P, Guignard B, et al.: Remifentanyl-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005; 103: 147-155.

Koppert W, Sittl R, Scheuber K, et al.: Differential modulation of remifentanyl-induced analgesia and postinfusion

hyperalgesia by S-ketamine and clonidine in humans.

Anesthesiology. 2003; 99: 152-159.

Guignard B, Bossard AE, Coste C, et al.: Acute tolerance:

Intraoperative remifentanyl increases postoperative pain and

morphine requirement. Anesthesiology. 2000; 93: 409-417.

Hensen EG, Duedahl TH, Romsing J, et al.: Intra-operative

remifentanil might influence pain levels in the immediate postoperative period after major abdominal surgery. Acta Anesth Scand. 2005; 49: 1464-1470.

Chu LF, Clark DJ, Angst MS: Opioid tolerance and hyperalgesia in chronic pain patients after one months of oral morphine therapy: A preliminary prospective study. J Pain. 2006; 7: 43-48.

Chen L, Malarick C, Seefeld L, et al.: Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain.

; 143: 65-70.

Cohen SP, Christo PJ, Wang S, et al.: The effect of opiod

dose and treatment duration on the perception of a painful

standardized clinical stimulus. Regional Anesth Pain Med. 2008; 33: 199-206.

Ram KC, Eisenberg E, Haddad M, et al.: Oral opioid use

alters DNIC but not cold pain perception in patients with

chronic pain. Pain. 2008; 139: 431-438.

Compton P, Charuvastra VC, Ling W: Pain intolerance in

opioid-maintained former opiate addicts: Effect of long-acting

maintenance agent. Drug Alcohol Depend. 2001; 63: 139-146.

Doverty M, White JM, Somogyi AA, et al.: Hyperalgesic

responses in methadone maintenance patients. Pain. 2001; 90: 91-96.

Pud D, Cohen D, Lawental E, et al.: Opioids and abnormal

pain perception: New evidence from a study of chronic opioid

addicts and healthy subjects. Drug Alcohol Depend. 2006; 82:


Crain SM, Shen KF: Acute thermal hyperalgesia elicited by

low-dose morphine in normal mice is blocked by ultra-low

dose naltrexone, unmasking potent opioid analgesia. Brain Res. 2001; 888: 75-82.

Holtman JR Jr, Wala EP: Characterization of morphine-induced hyperalgesia in male and female rats. Pain. 2005; 114: 62-74.

Juni A, Klein G, Kest B: Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: Evidence for multiple diverse hyperalgesic systems. Brain Res. 2006; 1070: 35-44.

Wala EP, Sloan PA, Holtman JR Jr: Effect of prior treatment

with ultra-low dose morphine on opioid- and nerve injuryinduced hyperalgesia in rats. J Opioid Manag. 2011; 7: 377-389.

Celerier E, Laukin JP, Corcuff JB, et al.: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci. 2001; 21: 4074-4080.

Laulin JP, Maurette P, Corcuff JE, et al.: The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg. 2002; 94: 1263-1269.

Movahedi S, Javan M, Ahmadiani A: Study on the possible

similar mechanism of ultra low dose–induced hyperalgesia and

development of tolerance to analgesia in male rats: Study based on the role of Gs signaling pathway. Physiol Pharmacol. 2006; 10: 107-114.

Pasternak GW: Multiple opiate receptors: Déjà vu all over

again. Neuropharmacology. 2004; 47: 312-323.

Pasternak GW: Molecular insights into opioid pharmacology: From the clinic to the bench. Clin J Pain. 2010; 26 (Suppl 10): S3-S9.

Bohn LM, Dykstra LA, Lefkowitz RJ, et al.: Relative opioid

efficacy the complements of the G-protein-coupled receptor

desensitization machinery. Mol Pharmacol. 2004; 66: 106-112.

Beaulieu JM: Morphine-induced -opioid receptor internalization: A paradox solved in neurons. J Neurosci. 2005; 25: 10061-10063.

Rajagopal S, Rajagopal K, Lefkowitz RJ: Teaching old receptors new tricks: Biasing seven-transmembrane receptors. Nat Rev Drug Discov. 2010; 9: 373-386.

Meert TF, Vermeirsch HA: A preclinical comparison

between different opioids: Antinociceptive versus adverse

effects. Pharmacol Biochem Behav. 2005; 80: 309-326.

Holtman JR Jr, Wala EP: Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav. 2006; 83: 100-108.

Hamann SR, Martin WR: Thermally evoked tail avoidance

reflex: Input-output relationship and their modulation. Brain

Res Bull. 1992; 29: 507-509.

Bennett GJ, Xie YK: A peripheral mononeuropathy in rat

that produces disorders of pain sensation like those seen in

man. Pain. 1988; 33: 87-107.

Randall LO, Selitto JJ: A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn

Ther.1957; 111: 409-419.

Esmaeilli-Machani S, Shimokawa N, Javan M: Low-dose

morphine induced hyperalgesia through activation of Gas protein kinase C and L-type Ca+2 channels in rats. J Neurosci Res. 2008; 86: 471-479.

Galeotti N, Stefano GB, Guarna M, et al.: Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain. 2006; 123: 294-305.

Juni A, Klein G, Kowalczyk B, et al.: Sex differences in hyperalgesia during morphine infusion: Effect of gonadectomy and estrogen treatment. Neuropharmacology. 2008; 54: 1264-1270.

McNaull B, Trang T, Sutak M, et al.: Inhibition of tolerance

to spinal morphine antinociception by low doses of opioid

receptor antagonists. Eur J Pharmacol. 2007; 560: 132-141.

Juni A, Cai M, Stankowa M, et al.: Sex-specific mediation of opioid-induced hyperalghesia by the melanocortin-1 receptor. Anesthesiology. 2010; 112: 181-188.

Crain SM, Shen KF: Antagonism of excitatory opioid receptor unctions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Brain Res. 2000; 84: 121-131.

Holtman JR Jr, Wala EP: Characterization of the antinociceptive and pronociceptive effects of methadone in rats. Anesthesiology. 2007; 107: 563-571.

Juni A, Klein G, Pintar JE, et al.: Nociception increases during opioid infusion in opioid receptor triple knock-out mice.

Neuroscience. 2007; 147: 439-444.

Waxman AR, Arout C, Caldwell M, et al.: Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Neurosci Lett. 2009; 462: 68-72.

Mao J, Song B, Ji RR, et al.: Chronic morphine induces

downregulation of spinal glutamate transporters: Implication in

morphine tolerance and abnormal pain sensitivity. J Neurosci.

; 22: 8312-8323.

Satoshi I, Minoru N, Seiko H, et al.: Defference in tolerance to antihyperalgesic effects between chronic treatment with morphine and fentanyl under a pain-like state. Jpn J Psychopharmacol. 2006; 26: 183-192.

Finn AK, Whisler JI: Endocitosis of the mu opioid receptor

reduces tolerance and a cellular hallmark of opiate withdrawal.

Neuron. 2001; 32: 829-839.

He L, Fong J, von Zastrow M, et al.: Regulation of opioid

receptor trafficking and morphine tolerance by receptor

oligomerization. Cell. 2002; 108: 271-282.

Johnson EE, Christe MJ, Connor M: The role of opioid receptor hosphorylation and trafficking in adaptations to persistent opioid treatment. Neurosignals. 2005; 14: 290-302.

Koch T, Widera A, Bartzsch K, et al.: Receptor endocytosis

counteract the development of opioid tolerance. Mol Pharmacol. 2005; 67: 280-287.

Bodnar RJ, Kest B: Sex differences in opioid analgesia,

hyperalgesia, tolerance and withdrawal: Central mechanism of

action and roles of gonadal hormones. Hormones Behav. 2010; 58: 72-81.

Craft RM, Mogil JS, Aloisi AM: Sex differences in pain and

analgesia: The role of gonadal hormones. Eur J Pharmacol.

; 8: 397-411.

Fillingim RB, Gear RW: Sex differences in opioid analgesia:

Clinical and experimental findings. Eur J Pain. 2004; 8: 13-25.

Tall JM, Stuesse SL, Cruce WL, et al.: Gender and the behavioral manifestations of neuropathic pain. Pharmacol Biochem Behav. 2001; 68: 99-194.

Yoshimatsu T, Moriyama K, Iwao Y, et al.: Involvement of

the mu-opioid receptor in opioid tolerance induced by the

intermittent administration of fentanyl in a rat chronic neuropathic pain model. J Kyorin Med Soc. 2011; 42: 62-69.

Benrath J, Brechtel C, Elke M, et al.: Low doses of fentanyl

block central sensitization in the rat spinal cord. Anesthesiology. 2004; 100: 1545-1551.

Rivat C, Laulin JP, Cocuff JB, et al.: Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methy-D-aspartate receptor antagonist, ketamine. Anesthesiology. 2001; 96: 381-391.

Richebe P, Rivat C, Laulin JP, et al.: Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats. Anesthesiology. 2005; 102: 421-428.

Chia YT, Liu K, Wang JJ, et al.: Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anesth. 1999; 46: 872-877.

Cooper DW, Linsay SL, Ryall DM, et al.: Does intrathecal

fentanyl produce acute cross-tolerance to i.v. morphine? Br J

Anesth. 1997; 78: 311-313.

Guignard B, Bossard AE, Coste C, et al.: The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg. 2002; 94: 1263-1269.

Guignard B, Coste C, Costes H, et al.: Supplementing desflurane-remifentanil anesthesia with small dose ketamine reduces perioperative opioid analgesc requirements. Anesth Analg. 2002; 95: 103-108.

Jung JY, Kim JH, Son SH: Effects of intraoperative continuous infusion of low dose remifentanyl and intravenous bolus dose of fentanyl on postoperative pain. Anesth Pain Med. 2011; 6: 138-142.

Latremoliere A, Woolf C: Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009; 10: 895-926.

Porreca P, Ossipov MH, Gebhart GF: Chronic pain and

medullary descending facilitation. Trends Neurosci. 2002; 25:


Zimmermann M: Pathobiology of neuropathic pain. Eur J

Pharmacol. 2001; 429: 23-37.

Ueda H: Molecular mechanisms of neuropathic pain phenotypic swich and initiation mechanisms. Pharmacol Ther. 2006; 109: 57-77.

Woolf CJ: Pain: Moving from symptom control toward

mechanism-specific pharmacologic management. Ann Intern

Med. 2004; 40: 441-451.

Burges SE, Gardell LR, Ossipov MH, et al.: Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci. 2002; 22: 5129-5136.

Gardell LR, Vanderah TW, Gardell SE, et al.: Enhanced

evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J Neurosci. 2003; 23: 8370-8379.

Liu T, van Rooijen N, Tracey DJ: Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain. 2000; 86: 25-32.

Mao J, Price DD, Hayes RL, et al.: Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res. 1992; 598: 271-278.

Raghavendra V, Tanga F, deLeo JA: Inhibition of microglial

activation attenuates the development but not existing

hipersensitivity in a rat model of neuropathy. J Pharmacol Exp

Ther. 2003; 306: 624-630.

Wang Z, Gardell LR, Ossipov MH, et al.: Pronociceptive

actions of dynorphin maintain chronic neuropathic pain.

J Neorosci. 2001; 21: 1779-1786.

Vallejo R, Tilley DM, Vogel L, et al.: The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010; 10: 167-184.

Joseph EK, Reichling DB, Levine JD: Shared mechanisms of opioid tolerance and transition to chronic pain. J Neurosci.

; 30: 4660-4666.

Chan MT, Wan AC, Gin T, et al.: Chronic postsurgical pain

after nitrous oxide anesthesia. Pain. 2011; 152: 2514-2520.

Grosu I, de Kock M: New concepts in acute pain management: strategies to prevent chronic postsurgical pain, opioid induced hyperalgesia, and outcome measures. Anesthesiol Clin. 2011; 29:311-327.

Katz J, Seltzer Z: Transition from acute to chronic postsurgical pain: Risk factors and protective factors. Expert Rev Neurother. 2009; 9:723-744.



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