Naloxone-Precipitated Acute Opioid Withdrawal Syndrome After Epidural Morphine

Sun, Hsiao Lun MD

Anesthesia & Analgesia:
doi: 10.1213/00000539-199803000-00019
Obstetric Anesthesia
Author Information

Department of Anesthesiology Cathay General Hospital, Taipei, Taiwan, Republic of China.

Accepted for publication November 19, 1997.

Address correspondence to Hsiao Lun Sun, MD, Department of Anesthesiology, Cathay General Hospital, 280 Section 4, Jen-Ai Rd., Taipei, Taiwan, Republic of China.

Article Outline

Epidural morphine provides substantial and prolonged postoperative pain relief but is associated with some troublesome side effects, such as pruritus, nausea and vomiting, urinary retention, and respiratory depression. Opioid antagonists have been used to prevent and manage these side effects with mixed results [1,2]. Previous human studies have demonstrated naloxone-precipitated withdrawal after brief parenteral morphine exposure [3,4]. However, the appearance of naloxone-precipitated withdrawal syndrome after a single dose of epidural morphine in an opioid-naive parturient has not been reported previously. This report describes an acute withdrawal syndrome precipitated by a naloxone injection for the treatment of pruritus eight hours after an epidural injection of morphine 2 mg.

Back to Top | Article Outline

Case Report

A 28-yr-old, primigravid, nulliparous woman underwent an elective cesarean section. She had no opioid exposure history or other significant medical disease. Epidural anesthesia was achieved with 2% lidocaine with epinephrine 1:200,000. After delivery, 2 mg of morphine in 10 mL of normal saline was administered epidurally. In the recovery room, 75 mg of diclofenac sodium was injected IM as an adjuvant for the relief of postcesarean pain. Eight hours after delivery, the patient complained of generalized pruritus and requested treatment. Naloxone 0.14 mg was administered IV in fractional doses. Two minutes later, she felt a warm sensation over both legs, and then spreading to the trunk and face. Pruritus resolved immediately and analgesia was preserved. However, the patient began to shiver approximately 5 min after the naloxone injection. The shaking waned within 30-45 s and waxed again every 1-2 min. She became restless and agitated. Tachypnea, lacrimation, and rhinorrhea were also found. The symptoms were not relieved immediately by IV diphenhydramine 30 mg but subsided gradually in 40 min without further treatment.

Back to Top | Article Outline


Opioid withdrawal syndrome is comprised of signs and symptoms including lacrimation, dilation of pupils, rhinorrhea, tachycardia, nausea, vomiting, yawning, sweating, increased respiration and body temperature, piloerection, restlessness, muscle tremor, and diarrhea [5]. Although it is generally thought that physical dependence develops only after chronic exposure to opioids, acute opioid withdrawal syndromes have been demonstrated in animals and humans by the administration of an opioid antagonist after short-term opioid exposure [3,6]. Schnur [6] observed signs of naloxone (0.4 or 1.0 mg/kg)-precipitated withdrawal in hamsters 70 minutes after a single dose of subcutaneous morphine (15 mg/kg) injection. Jones [3] demonstrated naloxone (0.14 or 0.28 mg/kg)-precipitated withdrawal syndrome 24 hours after a single dose of IM morphine (0.14 or 0.21 mg/kg) given to normal volunteers with no previous opioid experience. It is noteworthy that the doses of both drugs in these studies were relatively large.

In the management of epidural morphine-related side effects, opioid antagonists remain the most widely used drugs. Naloxone and nalbuphine have been used either therapeutically or prophylactically after epidural morphine 5 mg in obstetric anesthesia without the precipitation of withdrawal syndrome [2,7]. Clinically, a single dose of epidural morphine 2 mg is unlikely to incur physical dependence, and an injection of naloxone 0.14 mg is an established treatment for pruritus management. However, in the present report, the patient showed the characteristics of acute opioid withdrawal syndrome immediately after the naloxone injection, with abatement of these symptoms within 40 minutes. The temporal relation between the naloxone injection and the withdrawal syndrome strongly suggests cause and effect. It has been demonstrated that withdrawal precipitated by an opioid antagonist depends on the interval and dose of the opioid given and the dose of naloxone administered [8]. This is similar to Jones' observation that withdrawal symptoms appeared approximately 50-90 seconds after naloxone injection 24 hours postmorphine and disappeared completely 15 minutes after the injection. Naloxone has a short duration of action; its plasma half-life is approximately one hour, and its duration of effective antagonism is approximately 30-45 minutes [9]. This is consistent with the time course in this patient.

Apart from the precipitation of withdrawal syndrome in opioid-dependent patients, agitation, nausea, vomiting, hypertension, cardiac arrhythmias [10], and pulmonary edema [11] have been reported after naloxone reversal of opioid effects after general anesthesia. Additionally, Weintraub and Naulty [12] described an acute abstinence syndrome five minutes after the injection of 2 mg of epidural butorphanol in a parturient with concealed oxycodone medication history for one year. There were no withdrawal signs and symptoms observed in nondependent human subjects who received morphine placebo and naloxone challenge, whereas naloxone reliably precipitated withdrawal 6 and 12 hours postmorphine, which indicates that a short duration of opioid receptor occupancy by the agonist was necessary for the development of acute physical dependence [4,8]. Thus, opioid antagonists seem not to be innocuous in treating side effects related to morphine. Complete medical history and prudent clinical evaluation are essential to avoid the administration of an opioid antagonist to patient with a recent history of opioid exposure.

In summary, with the increasing use of epidural opioids for postoperative pain control, there is often a need for treatment of opioid-related side effects. In view of the case reported herein, the prophylactic or therapeutic use of opioid antagonists may precipitate symptoms of acute withdrawal after epidural morphine analgesia. Although it is rare, this potential complication of acute withdrawal syndrome cannot be overlooked. In clinical practice, caution should be used in administering opioid antagonists for the management of opioid-related side effects.

Back to Top | Article Outline


1. Gowan JD, Hurtig JB, Fraser RA, et al. Naloxone infusion after prophylactic epidural morphine: effects on incidence of postoperative side-effects and quality of analgesia. Can J Anaesth 1988;35:143-8.
2. Cohen SE, Ratner EF, Kreitzman TR, et al. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg 1992;75:747-52.
3. Jones RT. Dependence in non-addict humans after a single dose of morphine. In: Way EL, ed. Endogenous and exogenous opiate agonists and antagonists. New York: Pergamon Press, 1979:557-60.
4. Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA. Acute opioid physical dependence in humans: effects of naloxone at 6 and 24 hours postmorphine. Pharmacol Biochem Behav 1990;36:393-9.
5. Himmelsback CK. The morphine abstinence syndrome: its nature and treatment. Ann Intern Med 1941;15:829-39.
6. Schnur P. Acute morphine dependence in hamster. Pharmaco Biochem Behav 1991;38:711-3.
7. Kendrick WD, Wood AM, Daly MY, et al. Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus. Anesth Analg 1996;82:641-7.
8. Kirby KC, Stitzer ML, Heishman SJ. Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval II. J Pharmacol Exp Ther 1990;255:730-7.
9. Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone in rats and man: basis for its potency and short duration of action. Anesthesiology 1976;44:398-401.
10. Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979;58:524-5.
11. Flacke JW, Flacke WE, Williams GS. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977;47:376-8.
12. Weintraub SJ, Naulty JS. Acute abstinence syndrome after epidural injection of butorphanol. Anesth Analg 1985;64:452-3.
© 1998 International Anesthesia Research Society