Antinociceptive effect of a novel long-acting nalbuphine preparation{dagger}

K. S. Liu1,2, O. Y. P. Hu3, S. T. Ho4, J. I. Tzeng1, Y. W. Chen1 and J. J. Wang*,1

1 Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan. 2 Department of Chemistry, National Cheng Kung University, Tainan, Taiwan. 3 Department of Research and Education, National Defense Medical Center, Taipei, Taiwan. 4 Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan

*Corresponding author. E-mail: 400002{at}mail.chimei.org.tw
{dagger}This work was done in the Chi-Mei Medical Center, Tainan, Taiwan.

Accepted for publication: December 5, 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. A long-acting analgesic may be particularly desirable in patients suffering from long-lasting pain. The aim of the study was to evaluate the antinociceptive effect of a novel nalbuphine preparation and to determine its duration of action.

Methods. The antinociceptive effects of i.m. nalbuphine HCl in saline and nalbuphine base in sesame oil were evaluated in rats. The in vitro drug-releasing profiles of nalbuphine HCl and base in different preparations were also evaluated.

Results. We found that i.m. nalbuphine HCl 25, 50 and 100 µmol kg–1 produced dose-related antinociceptive effects with a duration of action of 1.5, 2 and 3 h, respectively. I.M. nalbuphine base 100, 200 and 400 µmol kg–1 also produced dose-related antinociceptive effects but with longer durations of action: 27, 49 and 55 h, respectively. In vitro studies demonstrated that nalbuphine base in sesame oil had the slowest drug-releasing profile of the different preparations.

Conclusions. I.M. injection of an oil formulation of nalbuphine base produced a long-lasting antinociceptive effect.

Br J Anaesth 2004; 92: 712–15

Keywords: analgesics opioid, nalbuphine; nerve, long-acting antinociception


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A long-lasting analgesic effect (i.e. a single dose with a 3–6-day duration of action) may be particularly desirable in patients suffering from long-lasting pain (e.g. postoperative pain, burn pain, post-tramatic pain, etc.) However, clinically available analgesics do not have such a long-lasting effect. Nalbuphine, (–)-17-(cyclobutyl-methyl)-4, 5{alpha}-epoxymorphinan-3,6{alpha},14-triol, is a morphine-like drug. It has agonist activity at {kappa}-opioid receptors and antagonist activity at µ-opioid receptors.13 As an analgesic, it is almost as potent as morphine and has been widely used in the treatment of clinical pain.17 Its main advantages over morphine are a ceiling effect on respiratory depression, low tolerance liability and a lack of significant withdrawal symptoms.13 It is available as injection for i.m. and i.v. administration, with recommended doses of 10–20 mg (25–50 µmol).27 However, nalbuphine is a short-acting drug with a duration of action of 3–5 h after i.v. or i.m. injection.27 In our laboratory, an oil formulation of nalbuphine base was made. The aim of the study was to evaluate whether this form had a long-lasting effect.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Two studies were carried out. In the first study the antinociceptive effects of i.m. nalbuphine HCl in saline and nalbuphine base in sesame oil were evaluated in rats. In the second study, the in vitro drug-releasing profiles of nalbuphine HCl and base in different preparations were evaluated.

Study 1
Male Sprague–Dawley rats, obtained from the National Science Council, Taiwan, weighing 175–225 g, were used. They were housed in groups of three for at least 1 week in a climate-controlled room maintained at 21°C with approximately 50% relative humidity. Lighting was on a 12-h light/dark cycle (lights on at 6.00 a.m.), with food and water available ad libitum up to the time of testing. All tests were performed in accordance with the recommendations and policies of the International Association for the Study of Pain and the protocol was approved by the Animal Investigation Committee of Chi-Mei Medical Center.

Nalbuphine HCl was purchased from Du Pont Merck (DE, USA). Nalbuphine base was obtained by precipitation. In brief, after addition of a saturated solution of Na2CO3 drop by drop into a nalbuphine HCl solution, nalbuphine base was precipitated. The precipitate was then filtered and washed several times with cold deionized water to remove excess Na2CO3. Nalbuphine base was obtained by drying the white residue and was then prepared in injectable sesame oil (Sigma, MO, USA) suspension. Nalbuphine HCl was prepared in water.

A paw pressure test was used to determine the antinociceptive effect of nalbuphine HCl and nalbuphine base.8 9 Briefly, the nociceptive threshold was measured by applying increasing pressure to the right hind paw using a TSE analgesia system (Randall-Selitto; Technical & Scientific Equipment GmbH, Bad Homburg, Germany). The nociceptive threshold (expressed in grams) was taken as the point that the rat made a vigorous attempt to remove the paw. A cut-off of 500 g was used.

Two dose–response studies were done (n=6 for each treatment). In the first we evaluated the antinociceptive effect of i.m. nalbuphine HCl at doses of 25, 50 and 100 µmol kg–1. The vehicle (saline) was used as control. In the second, we evaluated the antinociceptive effect of i.m. nalbuphine base at doses of 100, 200, and 400 µmol kg–1. The vehicle (sesame oil) was used as control. All drugs were injected into the left hind leg (biceps femoris and semitendinosus). Each rat received only one injection of 0.3 ml.

Study 2
An in vitro dialysis study was performed. A dialysis bag with a cut-off of 12 000–14 000 molecular weight (Union Carbide, IL, USA) was used. Before the test, phosphate buffer was prepared using monobasic potassium phosphate 1.9 g, dibasic sodium phosphate 8.1 g and sodium chloride 4.1 g dissolved in 1 litre of water to make an isotonic solution with a pH of 7.4. Nalbuphine HCl (100 µmol) or base (100 µmol) in 1 ml oil vehicle or phosphate buffer was put in the dialysis bag at the start of testing. Then, each of the different formulations (n=6 for each formulation) were put individually into a 200 ml flask containing 150 ml phosphate buffer and stirred at 500 rpm using a magnetic stirrer. The release of nalbuphine from each preparation (in the dialysis bag) into the phosphate buffer solution was measured. A UV spectrophotometer (UV-160, Shimadzu, Kyoto, Japan) was used to detect the nalbuphine concentration in the phosphate buffer outside the dialysis bag.

Statistical analysis
In Study 1 (the in vivo dose–response studies), the antinociceptive effects of nalbuphine HCl or base were compared with baseline values in the vehicle group using Student’s t-test. In the in vitro study (Study 2), we used repeated-measures ANOVA to compare the differences between the four groups. Bonferroni correction was applied for post hoc comparisons in a pair-wise manner. A P value less than 0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study 1
Nalbuphine HCl produced a dose-related antinociceptive effect after i.m. injection (Fig. 1). The duration of action of nalbuphine HCl 25, 50 and 100 µmol kg–1 was 1.5, 2 and 3 h, respectively (Fig. 1). A fourfold increase in dose produced a twofold (3 h/1.5 h) increase in duration of action. I.M. injection of nalbuphine base also produced a dose-related antinociceptive effect but with longer duration of action (Fig. 2): 27, 49 and 55 h at doses of 100, 200 and 400 µmol kg–1, respectively. A fourfold increase in dose produced a twofold (55 h/27 h) increase in duration of action. On an equimolar basis, i.m. injection of nalbuphine base 100 µmol kg–1 in sesame oil produced a longer duration of action (27 h) than nalbuphine HCl in saline (3 h).



View larger version (25K):
[in this window]
[in a new window]
 
Fig 1 Antinociceptive effects of i.m. nalbuphine HCl in saline (µmol kg–1) in rats (n=6 for each treatment) using the paw pressure test. Data are mean and SEM. *P<0.05 vs baseline values in the vehicle group (Student’s t-test).

 


View larger version (29K):
[in this window]
[in a new window]
 
Fig 2 Antinociceptive effects of i.m. nalbuphine base in sesame oil (µmol kg–1) in rats (n=6 for each treatment) using the paw pressure test. Data are mean and SEM. *P<0.05 vs baseline values in the vehicle group (Student’s t-test).

 
Study 2
The in vitro drug-releasing profiles of nalbuphine HCl or base in different preparations are shown in Figure 3. The results demonstrated that any two groups in the study were significantly different. The preparations of drugs in sesame oil had slower drug-releasing profiles than those prepared in phosphate buffer. Nalbuphine base in sesame oil had the slowest drug-releasing profile.



View larger version (28K):
[in this window]
[in a new window]
 
Fig 3 In vitro dialysis of different nalbuphine preparations (n=6 for each group). Data are percentage of nalbuphine that diffused out of the dialysis bag (mean and SD) and were analysed by repeated-measures ANOVA with Bonferroni correction. Results demonstrated that any two groups in the study were significantly different (P<0.01).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We found that i.m. injection of a novel nalbuphine preparation in rats produced a long-lasting effect, which was far longer than that of a traditional preparation of nalbuphine. An in vitro study also demonstrated that this novel nalbuphine preparation had a slow drug-releasing profile which supported this long-acting effect.

Opioid analgesics (e.g. morphine, meperidine and fentanyl) are frequently used for the management of clinical pain.1 These drugs interact with specific opioid receptors (i.e. µ receptors) in the central nervous system and exhibit potent analgesic activities. However, all these opioid analgesics have similar disadvantages.1 For long-term use, addiction is the most unwanted problem. Severe respiratory depression can also occur in some patients.1

Opioid agonist–antagonist analgesics have been used clinically for the management of pain.17 These are typically nalbuphine and butorphanol and exhibit dual agonist and antagonist activity at opioid receptors. For instance, nalbuphine has antagonist activity at µ-opioid receptors and agonist activity at {kappa}-opioid receptors.2 As a result of these pharmacological characteristics, the incidence of addiction and respiratory depression associated with their use is lower than with the pure opioid agonists. Equivalent doses of nalbuphine and butorphanol to morphine 10 mg are 10 mg and 2 mg, respectively.3 Among these drugs, nalbuphine is widely used clinically27 and it can be administered i.v. and i.m. but it is a short-acting drug. Extending the duration of action would make nalbuphine more valuable in clinical practice. A novel formulation of nalbuphine was made in our laboratory. In the present study, we found that this form had a long-lasting effect.

Pharmaceutically, pure opioid agonists are not considered to be good candidates for the preparation of long-acting formulations because of safety considerations. Pure opioid agonists such as morphine and fentanyl can cause severe respiratory depression in high doses, without a ceiling effect. It is a problem if a large amount of drug is accidentally released from the formulation into the blood stream. In contrast, mixed opioid agonist–antagonists are relatively safer and have a ceiling effect on respiratory depression.13

Pharmaceutically, the duration of action of a drug may be controlled by the chemical form (base or salt) of the drug, the physical state of the injection (suspension or solution) and the vehicle (oleaginous or aqueous solution) used. Drugs in base form are more oil soluble whereas drugs in salt form are more water soluble.10 11 Drugs have a longer duration of action in oleaginous solution than in aqueous solution. In order to obtain a longer duration of action, nalbuphine base was suspended in an oleaginous vehicle (sesame oil). Indeed, we found that the duration of action of this novel formulation was much longer. Moreover, we found that, among different preparations, nalbuphine base in sesame oil had the slowest drug-releasing profile, supporting the long duration action of this formulation in rats.

In our preparation, slow release of nalbuphine base from sesame oil is considered to be the mechanism of its long duration of action.10 11 However, at equimolar doses, short-acting formulations should produce a more potent effect (the magnitude of action) than a long-acting formulation. Following a higher dose, the potency of a long-acting formulation will be increased,1012 as demonstrated in our study (Figs 1 and 2).

Although a syringe or patient-controlled analgesia pump may be used to produce sustained analgesia in patients who require it, a single i.m. injection of a long-acting preparation has advantages over these methods: it reduces healthcare personnel time, it reduces the use of related medical products and it enhances patient convenience and compliance in daily activity.12

The safety of i.m. vegetable oils such as peanut, cotton seed and sesame oils is well documented.11 Several clinically available long-acting drugs are formulated in these preparations and injected i.m, for example estradiol valerate, fluphenazine decanoate, fluphenazine enanthate, progesterone, testosterone cypionate and testosterone enanthate.11 Most of these long-acting preparations are formulated in sesame oil and injected and this was used in our study.

In clinical practice, nalbuphine HCl 25 µmol (10 mg) i.m. provides an adult with 3–5 h analgesia (4 h average).27 In our study, i.m. injection of nalbuphine HCl 25 µmol kg–1 in rats had a 1.5 h duration of action. According to the ratio (2.7) obtained in humans and rats (4 h/1.5 h), we estimate that i.m. injection of nalbuphine base 100, 200 or 400 µmol in humans will have a duration of action of 3, 5.5 or 6.2 days.


    Acknowledgements
 
We express our appreciation to the Industrial Development Bureau, Ministry of Economic Affairs, Executive Yuan, Taiwan for funding. We also thank the Yung-Shin Pharmaceutical Industrial Company, Taiwan for assistance in the preparation of nalbuphine formulations.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbird LE, Goodman Gilman A, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 10th Edn. New York: McGraw-Hill, 2001; 569–620

2 Schmidt WK, Tam SW, Shotzberger GS, Smith DH Jr, Clark R, Vernier VG. Nalbuphine. Drug Alcohol Depend 1985; 14: 338–62

3 Hoskin PJ, Hanks GW. Opioid agonist-antagonist drugs in acute and chronic pain states. Drugs 1991; 41: 326–44[ISI][Medline]

4 Cohen RI, Edwards WT, Kezer EA, Ferrari DA, Liland AE, Smith ER. Serial intravenous doses of dezocine, morphine, and nalbuphine in the management of postoperative pain for outpatients. Anesth Analg 1993; 77: 533–9[Abstract]

5 Van den Berg AA, Montoya-Pelaez LF, Halliday EM, Hassan I, Baloch MS. Analgesia for adenotonsillectomy in children and young adults: a comparison of tramadol, pethidine and nalbuphine. Eur J Anaesth 1999; 16: 186–94[CrossRef][ISI][Medline]

6 Wang JJ, Ho ST, Tzeng JI. Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine-related side effect. Reg Anesth Pain Med 1998; 23: 479–84[ISI][Medline]

7 Woods MP, Rayburn WF, McIntosh DG, Scott JC Jr, Smith ML, Anderson JR. Nalbuphine after major gynecologic surgery. Comparison of patient-controlled analgesia and intramuscular injections. J Reprod Med 1991; 36: 647–50[ISI][Medline]

8 Begon S, Pickering G, Eschalier A, Dubray C. Magnesium increases morphine analgesic effect in different experimental models of pain. Anesthesiology 2002; 96: 627–32[ISI][Medline]

9 Perrot S, Guillbaud G, Kayser V. Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation. Anesthesiology 2001; 94: 870–5[CrossRef][ISI][Medline]

10 Ansel HC, Allen Jr. LV, Popovich NG. Dosage form design: biopharmaceutic and pharmacokinetic considerations. In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edn. Philadelphia: Lippincott Willams & Wilkins, 1999; 101–41

11 Ansel HC, Allen Jr LV, Popovich NG. Parenterals. In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edn. Philadelphia: Lippincott Willams & Wilkins, 1999; 397–449

12 Ansel HC, Allen Jr LV, Popovich NG. Modified-release dosage forms and drug delivery systems. In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edn. Philadelphia: Lippincott Willams & Wilkins, 1999; 229–43





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
92/5/712    most recent
aeh126v1
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Liu, K. S.
Articles by Wang, J. J.
PubMed
PubMed Citation
Articles by Liu, K. S.
Articles by Wang, J. J.