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Open-Label Exploration of an Intravenous Nalbuphine and Naloxone Mixture as an Analgesic Agent Following Gynecologic Surgery

Assaf T. Gordon MD, Jon D. Levine MD, PhD, Michel Y. Dubois MD, Robert D'Angelo MD, Ann M. Conlon RN, Danijela Levacic MD, Allen Lebovits PhD
DOI: http://dx.doi.org/10.1111/j.1526-4637.2006.00229.x 525-530 First published online: 1 September 2007


Objective. The purpose of this series was to explore a 12.5:1 fixed-dose ratio of an intravenous nalbuphine and naloxone mixture (NNM) for use in patients following gynecologic surgery.

Design and Patients. Open-label, nonrandomized case series. The first series was a dose-ranging investigation for 12 patients following elective total abdominal hysterectomy or myomectomy. In this series, fentanyl was used for intraoperative analgesia, and patients were assigned to a lower NNM (2.5 mg/0.2 mg) or to a higher NNM (5 mg/0.4 mg) dose group. The second series evaluated the fixed dose of 5 mg nalbuphine/0.4 mg naloxone for four patients undergoing ambulatory gynecologic procedures. In the second series, no opioid agents were administered intraoperatively to eliminate the possibility of mu-opioid reversal by naloxone postoperatively.

Outcome Measures. Pain control was assessed using a Verbal Pain Scale (0–10). Vital signs, side effects, and adverse events were recorded to determine drug safety.

Results. In the first series, there were no adverse events; however, each patient required rescue medication (either morphine or fentanyl). In the second series, two of the four patients reported a reduction in pain following drug administration and did not require any further analgesic agents in the 3-hour postoperative period. One patient had an asymptomatic lowering of heart rate after receiving the drug.

Conclusion. Additional research of the unique combination therapy of nalbuphine and naloxone is warranted to further determine its potential clinical efficacy and safety.

  • Nalbuphine
  • Naloxone
  • Kappa Receptor
  • Opioid
  • Pain
  • Agonist–Antagonist


The search for potent perioperative analgesia with fewer mu-opioid side effects has led to significant interest in mixed receptor agonist/antagonist mixtures [1,2]. The experimental combination (nalbuphine and naloxone mixture—NNM) in this report is a fixed ratio of the kappa-opioid agonist and weak mu-antagonist nalbuphine (Nab) and mu-antagonist naloxone (Nlx). In a randomized, placebo-controlled, double-blinded series, Gear et al. found an unexpected anti-analgesia in men receiving Nab alone following bony-impacted third molar extraction, compared with women, who exhibited a dose-dependent analgesic response [3]. To determine whether Nab anti-analgesia is opioid receptor mediated, Gear et al. combined low-dose Nlx with Nab in patients following third molar extraction and discovered a reversal of the anti-analgesia in men, and an enhancement of analgesia in women [4].

Following this initial investigation, Gear and colleagues [3–7] explored the use of Nab in mixture with Nlx for treating dental postoperative and trigeminal neuropathic pain with encouraging results, including dose-ranging studies that suggested the most effective ratio of Nab to Nlx to be 12.5:1 [5,6]. The mechanism for the enhanced kappa opioid effect may be due to a dual action of Nab and Nlx on different opioid receptor subtypes: a Nax-sensitive anti-analgesic receptor and a Nax-insensitive kappa receptor (Figure 1).

Figure 1

Proposed dual-action mechanism of the opioid antagonist naloxone producing enhanced nalbuphine analgesia: A) naloxone is an opioid antagonist, which at low doses selectively antagonizes the action of nalbuphine at an antinalgesia receptor; B) the kappa agonist nalbuphine also acts on a receptor that is less sensitive to naloxone to produce analgesia. Block arrow = agonist; dashed line = antagonism.

The purpose of the present report is to describe two preliminary case series designed to explore the use of intravenous NNM as a perioperative analgesic agent for women undergoing gynecologic surgery.


This series was an open-label clinical investigation using a fixed-dose ratio of 12.5:1 Nab/Nlx. The criteria for inclusion included women undergoing gynecologic surgery, ages 18–65, American Society of Anesthesiology physical status 1–3, and stable postoperative condition. Patients were excluded if they had other serious medical conditions. For both series, a standard anesthetic regimen was followed that included antiemetic agents prior to surgery. Patients received their first dose of NNM postoperatively once stable and awake, and reporting moderate postoperative pain (≥2 on Categorical Pain Intensity Scale, 0–3). Efficacy was assessed by Verbal Pain Scale (VPS, 0–10) every 5–10 minutes for the first 30 minutes, and then 30–60 minutes thereafter. Throughout the study period, vital signs, side effects, and adverse events were recorded every 10–15 minutes for the first 2 hours and then every 30–60 minutes to determine drug safety. Patients requiring additional analgesia due to inadequate pain relief were offered a rescue medication (fentanyl or morphine).

Approval for both series was granted by the Institutional Review Boards of both sponsoring institutions, and informed consent was obtained from each participant.

Case Series A

The first series was a dose-ranging investigation conducted in female patients undergoing elective total abdominal hysterectomy or myomectomy. A total of 12 patients were enrolled, with six in a lower (2.5 mg/0.2 mg) and six in a higher (5 mg/0.4 mg) dose group. Intraoperatively, the anesthesiologist administered between 250 and 900 µg of fentanyl for pain control. Each patient received a standardized initial infusion of NNM (slow intravenous push over 2 minutes) for pain once awake and stable after surgery. If adequate pain relief was not obtained 10 minutes after the initial dose, a second dose was administered.

Case Series B

To remove the possibility of mu-opioid reversal of the Nlx in NNM by intraoperative fentanyl, a possible hindrance to clinical efficacy, a limited pilot study was undertaken for case series B, in which 5 mg/0.4 mg NNM (rather than fentanyl) was administered preoperatively. As both doses were administered without adverse events in case series A, only the higher 5-mg Nab/0.4-mg Nlx fixed dose (slow intravenous push over 2 minutes) was chosen for study in case series B, due to greater theoretical likelihood of producing effective analgesia. Ambulatory gynecologic procedures were chosen for case series B, with the expectation of less intense postoperative pain as compared with hysterectomy and myomectomy. This decision was made as NNM had been shown to be effective in ambulatory dental procedures in previous studies [3–5]. Analgesia during surgery was managed through titration of primary inhalation or intravenous nonopioid anesthesia (propofol, midazolam) rather than by opioid agents, thereby eliminating the possibility of mu-opioid reversal postoperatively. The study was completed after enrollment of four patients. Importantly, no adverse events halted the investigation.


In case series A, all patients required rescue medications within 50 minutes after the initial postoperative dose (Figure 2). Each patient received a total of two postoperative doses of NNM, with patient pretreatment VPS scores ranging between 5 and 10 (Figure 2). No adverse events were related to the administration of the drug. VPS scores at the time of rescue ranged between 7 and 10, and rescue medication produced analgesia in all patients.

Figure 2

Change in VPS after administration of postoperative dose of drug for the 12 patients in case series A. Figure legend reports demographics, surgery type, surgery length, and time from the secondary postoperative NNM dose until the need for rescue medication. Time 0 = baseline VPS recorded just prior to NNM administration; My = myomectomy; TH = total abdominal hysterectomy; L = low-dose group––Nlb 2.5 mg/Nax 0.2 mg; H = high-dose group––Nlb 5 mg/Nax 0.4 mg.

In case series B, four patients were enrolled, with each patient receiving a single intravenous dose 10 minutes prior to induction of anesthesia and a single dose after surgery, once awake and having postoperative pain (Figure 3). Two of the four patients reported reduced pain following NNM administration and completed the 3-hour postoperative observation without requiring any rescue medication. The other two subjects had verbal pain scores that did not decrease in the 30 minutes after NNM administration, and required rescue medication with a mu-opioid (Figure 2). Subject 2 had an episode of bradycardia (heart rate [HR] < 60) 1 minute post NNM administration (preoperatively, the HR was 76). Subject 2 had this symptom for 49 minutes; with the HR recorded as 50, 51, and 44 (15 minutes apart), with an increase in the HR to 63 within 5 minutes after 1 dose of 0.2-mg intravenous glycopyrollate. Three of the four patients had mild pain at intravenous site during administration that resolved in 5 minutes.

Figure 3

Change in VPS after administration of postoperative dose of drug for the four patients in case series B. Time 0 = Baseline VPS recorded just prior to NNM administration. VPS reporting halted after rescue medication given. Figure legend reports demographics, surgery type, surgery length, and time from the secondary postoperative NNM dose until the need for rescue medication. D/C = dilatation and curettage; H = hysteroscopy; L = laparoscopy; OC = ovarian cystectomy; P = polypectomy; n/a = not applicable as patient did not require rescue; H = high-dose group––Nlb 5 mg/Nax 0.4 mg.


The present report describes two preliminary case series using intravenous NNM as a perioperative analgesic agent for women undergoing gynecologic surgery. Previous studies have demonstrated significant postoperative analgesia using NNM without intraoperative opioid [3–5]. The use of intraoperative mu-receptor agonists during total abdominal hysterectomy and myomectomy in our first series resulted in no demonstrable analgesic effect of NNM, with all patients requiring rescue medication. In case series B, NNM may have had an analgesic effect for two subjects; however, no conclusions can be made given the lack of placebo or group comparisons. The range of response to NNM in case series B cannot be accounted for in the current study given the preliminary nature of having only four patients receive the medication. Procedure selection may be important for future study, as case series B was conducted in patients undergoing ambulatory surgery with lower pre-drug VPS scores (mean 4.3) compared with those in case series A (mean 7.6).

In administering a combination agent, the dose ratio of the Nab and Nlx is a critical aspect to optimizing the balance between effective analgesia, analgesia reversal, and reduction of mu-related side effects. The rationale for the fixed Nab : Nlx ratio of 12.5:1 was established through studies by Levine and colleagues [4–6] in a postoperative dental model. Across several studies, five groups of patients (each group N ≈ 30, equally divided into men and women) received the Nab + Nlx mixture in doses of 0 mg + 0.4 mg (0:1), 2.5 mg + 0.4 mg (6.25:1), 2.5 mg + 0.2 mg (12.5:1), 5 mg + 0.4 mg (12.5:1), and 10 mg + 0.4 mg (25:1) following third molar dental extraction. The combination was matched to control groups of equal doses of Nab alone. The Nab : Nlx ratio of 12.5:1 produced the most significant analgesia in both men and women. The anti-analgesic effect of Nab alone was present at both 2.5 mg and 5 mg; however, the 12.5:1 ratio combination with Nlx effectively inhibited nalbuphine's anti-analgesic effect while allowing its kappa-mediated analgesia to be expressed.

No adverse events or side effects occurred in case series A. One patient in case series B had an episode of bradycardia following NNM administration. The mechanism for this reduction of HR is not completely understood. Bradycardia may have been associated with mu-receptor-induced histamine release and vagomimetic action, or central kappa-opioid pressor response that can occur with a potential baroreflex-evoked bradycardia [8]. Of note, no acute nausea or vomiting occurred with NNM administration.

Proof-of-principal that optimized-dose ratios of mixture therapy can maintain opiate analgesic effects while reducing unwanted side effects has been established previously. In postsurgical patients using patient-controlled analgesia, an “ultralow” concentration of naloxone (0.6 µg/mL) in mixture with morphine (1 mg/mL) has been shown to be equianalgesic to morphine alone, but with reduced pruritus, nausea, and vomiting [9]. A previous series by the same authors noted that “low” doses of naloxone (10 times greater than “ultralow” dose) resulted in hyperalgesia and no change in side-effect profile, suggesting the importance of optimal naloxone dosing to morphine ratio to achieve desired effects [10,11]. Like naloxone, nalbuphine's mu-antagonist qualities have been tested in mixture with morphine and hydromorphone, with postsurgical patients reporting equal analgesia and decreased pruritus, nausea/vomiting, and urinary retention [12,13]. Optimum dosing of nalbuphine was also critical to achieving favorable outcomes, with lower or higher doses resulting in no change in side-effect profile or increased patient-controlled analgesia demands [12,14]. Another effective use of a mixture agent with naloxone has been demonstrated in maintenance therapy for opiate addiction and acute opiate withdrawal, with mixture agents such as buprenorphine/Nlx [15–17] and lofexidine/Nlx [18].

Much attention has been given to sex differences in opioid antinociception and mixed action of the kappa agonists in animal models and clinical trials. While there are conflicting reports in the literature, evidence suggests that kappa agonists, such as nalbuphine, pentazonine, and butorphanol, may have lower efficacy at the mu receptor in females than in males, but higher efficacy at the kappa receptor in females [3,5,19,20].


NNM was administered without serious adverse side effects in our patient population and warrants further investigation in placebo-controlled and adequately powered studies. Agonist/antagonist mixtures have been shown to provide potent analgesia and reduced mu-related side effects in previous studies. Given the small number of patients in both series and the limited patient response, further research is needed to establish the clinical usefulness of a fixed-ratio formulation of Nab and Nlx for treatment of postoperative pain.


Grant support for the completion of the study and supply of NNM were provided by Renovis Inc. (San Francisco, CA). Jon Levine is a member of the Medical and Scientific Advisory Board, Renovis Inc., and is named on a patent related to the NNM.


We would like to thank William K. Schmidt, PhD, Vice President of Clinical Research, Renovis, Inc., for logistical support and the sharing of study information.


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