This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Siniscalchi, A. Articles by Martinelli, G. Search for Related Content PubMed PubMed Citation Articles by Siniscalchi, A. Articles by Martinelli, G. Related Collections Complications Pain Medicine Clinical Pharmacology Pain

---

PAIN MEDICINE

Opioid-Induced Hyperalgesia and Rapid Opioid Detoxification After Tacrolimus Administration

Antonio Siniscalchi, MD, Emanuele Piraccini, MD^*, Zuzana Miklosova, MD^*, Stefania Taddei, MD, Stefano Faenza, MD, Mph^*, and Gerardo Martinelli, MD, Mph^*

From the Department of Anesthesiology, *University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy.

Address correspondence and reprint requests to Emanuele Piraccini, Department of Anesthesiology, S.Orsola-Malpighi Hospital, via Massarenti 9, 40137 Bologna, Italy. Address e-mail to dremanuelepiraccini{at}yahoo.it.

	Abstract

Top Abstract Introduction CASE REPORT DISCUSSION REFERENCES

 
Opioids can induce central sensitization and hyperalgesia, referred to as "opioid-induced hyperalgesia." Our report describes a patient who underwent intestinal transplant followed by immunosuppressant-related neuropathic pain. Her pain was treated with limited success over the course of 3 yr with different therapies, including IV morphine. She developed opioid-induced hyperalgesia, which was successfully treated with rapid detoxification under general anesthesia. Detoxification improved her quality of life, including the ability to resume physiotherapy. Six months after treatment, she remained opioid free. Our experience suggests that rapid detoxification under general anesthesia may be an effective treatment for opioid-induced hyperalgesia and merits comparison to traditional detoxification methods.

	Introduction

Top Abstract Introduction CASE REPORT DISCUSSION REFERENCES

 
Opioids are mainstays in the management of moderate to severe pain. It has recently become clear that opioids can induce central sensitization and hyperalgesia.1 There is no agreed upon treatment for opioid-induced hyperalgesia. In this case report, we share our experience treating a patient with opioid-induced hyperalgesia after long-term opioid treatment of neuropathic pain.

	CASE REPORT

Top Abstract Introduction CASE REPORT DISCUSSION REFERENCES

 
A 27-yr-old woman underwent intestinal transplant for chronic, idiopathic intestinal pseudo-obstruction disease at age 21 yr, followed by chronic immunosuppressant therapy with tacrolimus (target plasma concentration = 15–20 ng/mL) as per our protocol.2 She also received IV aminoglycosides and corticosteroids. After 8 mo, she developed a sensory-motor neuropathy characterized by severe pain, sometimes lancinating and scorching, paresthesias in her legs and arms, absence of reflexes, and asthenia. This is a well-known complication of tacrolimus, especially if administrated at high doses and associated with other drugs with potential neurotoxic effects, including IV aminoglycosides and corticosteroids.3–7

Six months of multimodal therapy8,9 with gabapentin (1800 mg/d), lorazepam (2 mg/d), and amitriptyline (20 mg/d) did not adequately treat her pain. We stopped the lorazepam, reduced the gabapentin dose to 600 mg/d, continued the amitriptyline, and initiated IV morphine therapy, 15 mg/d divided into three boluses. This controlled her pain, to a visual analog scale (VAS) score of 3 on a 0 to 10 scale. After 5 mo, she started developing tolerance, requiring increasing morphine doses.

She continued this therapy for 2 yr, with the morphine dose escalating to 100 mg/d. However, the result was unsatisfactory. The morphine causes considerable drowsiness. Additionally, her pain became severe, with a VAS score of 9, particularly in her legs and forearms. The severe pain precluded any kind of movement, included physiotherapy, and did not respond to further increases in morphine.

We tried to switch the patient from morphine to oral methadone, starting at 20 mg/d accompanied by decreasing morphine administration. This resulted in intolerable pain (VAS score = 10) and was abandoned. We next turned to spinal cord stimulation10 to reduce her leg pain and allow physiotherapy. After placement of two paramedian epidural electrodes from T12-L1 to L3–4, her pain decreased to a VAS score of 4–5, and her morphine was reduced to 40 mg/d.

Six months later, the patient developed hyperalgesia in her legs, referred also to her back, with an increase in VAS score to 7–8. Increases in her daily IV morphine to 100 mg/d did not alleviate her symptoms. We suspected that her hyperalgesia was a consequence of her longstanding morphine treatment, and decided to pursue opioid detoxification.

Opioid Detoxification
We choose a moderately rapid detoxification protocol under general anesthesia over a course of 5 d. We believed that an excessive hemodynamic response could have been deleterious to her transplanted intestines, and thus excluded ultra rapid opioid detoxification. Our goal was the absence of any autonomic response for three consecutive naloxone challenges, administered once/day, before awakening the patient. The 3-day duration was chosen to permit full washout of systemic morphine. One day before we began detoxification, the patient received IM midazolam 0.1 mg/kg and clonidine 3 µg/kg. On the day of detoxification, before induction of general anesthesia, the patient was started on a continuous IV infusion of clonidine 2 µg · kg^–1 · h^–1, which was continued until hospital discharge. The patient was also given an IV bolus of ranitidine 3 mg/kg and omeprazole 40 mg, which were repeated daily until discharge.

General anesthesia was induced with IV propofol 2 mg/kg. After tracheal intubation, the patient was ventilated with an air/oxygen mixture. Propofol was initially infused at 6 mg · kg^–1 · h^–1 and titrated to clinical signs of anesthetic adequacy (e.g., keeping the patient unconscious, and minimizing hemodynamic and movement response). Morphine administration was reduced by 50% on the first day, and was terminated on the second day.

After 3 days of general anesthesia, the propofol infusion was reduced to 3 mg · kg^–1 · h^–1 and an IV bolus of naloxone 0.01 mg/kg was administrated to test the patient's response, after which the propofol infusion was returned to its prior rate. No autonomic response was observed. The challenge was repeated on day 4 and day 5. These challenges also did not result in any autonomic response. At the end of the fifth day, we started an IV infusion of naloxone, 0.8 mg/d, and awakened the patient.

During the first 2 days after awakening, the patient appeared drowsy. Her pain was dramatically reduced, with a VAS score of 4. Her clonidine administration was stopped during the second day for 12 h due to an episode of hypotension, after which it was restarted and maintained for the following week. She required a single dose of IV diazepam 5 mg for anxiety. The naloxone infusion was continued for 3 days, and the patient did not receive additional opioids.

After hospital discharge, the patient's VAS score was 2, characterized by superficial hypoesthesia and limited to her legs. She was able to resume physical therapy. Her only pain medication is oral gabapentin, 600 mg/d.

	DISCUSSION

Top Abstract Introduction CASE REPORT DISCUSSION REFERENCES

 
The treatment of any chronic pain syndrome is challenging, often requiring a multimodal approach. As our patient was initially refractory to non-opioid pain management, we elected to use IV morphine, which transiently helped her pain condition. However, eventually we were confronted with a pain state refractory to escalating morphine, and characterized by hyperalgesia.

Our initial attempt to substitute methadone for morphine failed, possibly because of inadequate methadone dosing. We eventually felt that the best therapeutic alternative was opioid detoxification under general anesthesia. Certainly our patient did not have the psychological issues that may complicate opioid detoxification in patients who abuse opioids.11–13 Indeed, she was strongly motivated to terminate her opioid therapy and to seek improved pain management.

This case presented a host of problems in the management of chronic neuropathic pain. In our view, opioid detoxification under general anesthesia may be an effective modality for the patient receiving chronic opioid maintenance, who develops hyperalgesia, and thus merits formal study for safety and efficacy in this population.

	Footnotes

 
Accepted for publication October 3, 2007.

	REFERENCES

Top Abstract Introduction CASE REPORT DISCUSSION REFERENCES

 

1. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87[Web of Science][Medline]
2. Masetti M, Cautero N, Lauro A, Di Benedetto F, Begliomini B, Siniscalchi A, Pironi L, Miglioli M, Bagni A, Pinna AD. Three-year experience in clinical intestinal transplantation. Transplant Proc 2004;36:309–11[Web of Science][Medline]
3. Peltier AC, Russell JW: Recent Advances in drug-induced neuropathies. Curr Opin Neurol 2002;15:633–638[Web of Science][Medline]
4. Bechstein WO. Neurotoxicity of calcineurin inhibitors impact and clinical management. Transpl Int 2000;13:313–26[Web of Science][Medline]
5. Wijdicks E. Neurotoxicity of immunosuppressive drugs. Liver Transpl 2001;7:937–42[Web of Science][Medline]
6. Ayres RC, Dousset B, Wixon S, Buckels JA, McMaster P, Mayer AD. Peripheral neurotoxicity with tacrolimus. Lancet 1994;343:862–3[Web of Science][Medline]
7. Wilson JR, Conwit RA, Eidelman BH, Starzl T, Abu-Elmagd K. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve 1994;17:528–32[Web of Science][Medline]
8. Vadalouca A, Siafaka I, Argyra E, Vrachnou E, Moka E. Tharapeutic management of chronic neuropatic pain: an examination of pharmacologic treatent. Ann NY Acad Sci 2006;1088:164–86[Web of Science][Medline]
9. Gilron I, Bailey JM, Dongsheng T, Holden RR, Weaver DF, Houlden R. Morphine, Gabapentin, or their combination for neuropathic pain. New Engl J Med 2005;352:1324–34[Abstract/Free Full Text]
10. Costantini A. Spinal cord stimulation. Minerva Anestesiol 2005;71(7–8):471–4[Medline]
11. Krabbe PF, Koning JP, Heinen N, Laheij RJ, Van Casuter RM, De Jong CA. Rapid detoxification from opioid dependence under general anesthesia versus standard methadone tapering: abstinence rates and withdrawal distress experiences. Addict Biol 2003;8:351–8[Web of Science][Medline]
12. Favrat B, Zimmermann G, Zullino D, Krenz S, Dorogy F, Muller J, Zwahlen A, Besson J. Opioid detoxification under general anesthesia versus traditional clonidine detoxification combined with an additional week of psychosocial support: A randomized clinical trial. Drug Alcohol Dependence 2006;81:109–16[Web of Science][Medline]
13. Gowing L, Ali R, White J: Opioid antagonist under heavy sedation or anesthesia for opioid withdrawal. Cochrane Database Syst Rev 2006;19:0020022

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Siniscalchi, A. Articles by Martinelli, G. Search for Related Content PubMed PubMed Citation Articles by Siniscalchi, A. Articles by Martinelli, G. Related Collections Complications Pain Medicine Clinical Pharmacology Pain