Effect of Buprenorphine on Postoperative Pain Levels

ABSTRACT

In recent years, buprenorphine has become an increasingly popular choice for managing opioid dependence; however, buprenorphine’s unique mechanism of action can make treating acute pain more complicated. In opioid-dependent patients managed with buprenorphine, would continuing buprenorphine therapy during the perioperative period affect postoperative pain levels? The research method for this study is a formal literature review. I predict that continuing buprenorphine throughout the perioperative period will improve postoperative pain levels in opioid-dependent patients maintained on buprenorphine.

INTRODUCTION

In recent years, buprenorphine has become an increasingly popular choice in the treatment of opioid dependence. Even though it is a partial mu agonist, buprenorphine is known to have high mu-receptor affinity. When buprenorphine is continued throughout the perioperative period, this property may reduce the effectiveness of other full mu agonist opioids. As a result, this pharmacological trait introduces an obstacle for successful treatment of acute surgical pain in the patient taking chronic buprenorphine. The clinician must choose the best option for this patient, to continue or discontinue buprenorphine therapy during the perioperative period.

BACKGROUND AND SIGNIFICANCE

It is imperative to establish evidence-based practice guidelines regarding the best method of acute pain management for patients taking chronic buprenorphine. As buprenorphine use increases, healthcare providers will encounter opioid-dependent patients taking chronic buprenorphine with higher frequency in the surgical setting.¹ Although the positive outcomes of buprenorphine use are comprehensively researched and well documented, the evidence regarding the perioperative continuation or suspension of buprenorphine is limited and inconsistent. As a result, prescribers may avoid buprenorphine altogether, ultimately preventing more patients from receiving a potentially superior treatment.

Perioperative is defined as the phase immediately prior, during, and immediately after a surgical procedure. Postoperative period is defined as the phase after a surgical procedure is performed. Buprenorphine maintenance therapy (BMT) is defined as a sustained dose of buprenorphine taken by an opioid-dependent patient for an indefinite period of time. Methadone maintenance therapy (BMT) is defined as a sustained dose of methadone taken by an opioid-dependent patient for an indefinite period of time. Full mu opioid agonists activate mu receptors until a maximum effect is reached or the receptor is fully activated. Methadone, morphine, and oxycodone are examples of full mu agonists. Partial mu opioid agonists bind to receptors and partially activate them, but not to the same degree as do full agonists. Partial mu agonists can also displace full mu agonists from receptors. Buprenorphine is a partial mu agonist. Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief.

METHODS

The research method for this study was a formal literature review. The purpose of this study was to answer the question, in opioid-dependent patients managed with buprenorphine, would continuing buprenorphine therapy during the perioperative period affect postoperative pain levels? I searched the database SuperSearch. The key terms for this search were (pain management OR treatment), buprenorphine, and (perioperative OR intraoperative OR postoperative) using the Boolean operator AND. I limited results to peer-reviewed academic journal articles published in English from 2004-2014. Initial results were refined using the inclusion criteria of patients maintained on buprenorphine therapy prior to surgery and perioperative pain management, and the exclusion criteria of animal studies and buprenorphine administration techniques: epidural, intrathecal, perineural, subcutaneous, and transdermal.

REVIEW OF THE LITERATURE

The purpose of these studies is to examine perioperative acute pain management in opioid-tolerant patients taking BMT.

The type of studies include a retrospective cohort study, literature reviews, and case reports examining a population of people taking chronic buprenorphine.

Buprenorphine may be a more preferable method than methadone for chronic opioid replacement therapy. The use of buprenorphine has been associated with improvement in education, social life, and toxicological conditions when compared to methadone.¹ Buprenorphine is also perceived to have less adverse effects and social stigma than methadone.² In addition, buprenorphine’s full opioid agonist effects are lower compared to methadone, improving its safety profile.³ Buprenorphine may also induce less hyperalgesia than full agonists, although this has yet to be confirmed.² In support of this statement, however, Koppert et al⁴ found that the antihyperalgesic effects of buprenorphine were stronger and of longer duration as compared with the pure mu receptor agonist studied in the same model.

Though some researchers recommend a transition from buprenorphine to a full mu agonist preoperatively, an interruption in BMT is not ideal. A drug holiday or transition to other chronic opioids, such as methadone, prior to surgery may lead to simplified sedation techniques; however, it is time consuming and unnecessary, and alternatives should be considered.¹ It is best that patients with opioid dependence be in some early withdrawal before initiating treatment with buprenorphine.⁵ As a result, when a patient transitioned to methadone prior to surgery returns to their previous dose of buprenorphine postoperatively, withdrawal may occur.¹ Additionally, for patients switched from BMT to MMT preoperatively, methadone must be ceased for at least 36 hours and the patient should experience mild withdrawal symptoms before buprenorphine is restarted.⁶ In contrast to these recommendations, the retention of buprenorphine was found to be better in heroin addicts with less morbidity if buprenorphine was not rapidly withdrawn, but continued for up to 350 days.⁵

When chronic buprenorphine doses were continued throughout perioperative period, patients were able to achieve good pain control with additional opioids and/or additional buprenorphine doses. In a small series of 5 patients, adequate pain control was achieved when other full mu agonist opioids were given as needed in addition to the patient’s usual daily dose of buprenorphine.⁷ In another study,⁸ the patient achieved adequate pain control on postoperative day 1 and 2 with a total daily buprenorphine dose of 72 mg, and was able to successfully and comfortable taper to her baseline dose of 24 mg/d by day 11. Furthermore, Jones et al⁹ reported the buprenorphine-managed patient scored 0 out of 10 on all 6 post morphine-PCA pain assessments, and 0 to 5 out of 10 on all post discharge pain assessments while taking buprenorphine and oxycodone/acetaminophen.

Only 1 study¹⁰ reported severe postoperative pain control with the continuation of buprenorphine during the perioperative period. The study¹⁰ highlighted a case report for one patient with Type I Chiari malformation receiving buprenorphine for chronic pain who underwent two identical surgical procedures. For the first procedure, the patient’s usual dose of buprenorphine was continued throughout the perioperative period, and a full mu agonist was used for postoperative pain.¹⁰ The patient reported severe postoperative pain after this procedure.¹⁰ This information is limited, however, by self-report. No documentation was obtained from the outside hospital where the first procedure was performed.¹⁰ The author is a representative for the hospital where the second procedure was performed.¹⁰ For the second procedure, the patient’s buprenorphine was discontinued 5 days prior to surgery, and the patient was transitioned to a full opioid agonsist.¹⁰ Again, the patient’s postoperative pain was managed with a full opioid receptor agonist.¹⁰ Though the patient reported acceptable pain control on postoperative day 1, the patient’s pain was reported at 7 to 8/10 immediately after surgery.¹⁰

Although some researchers suggest that buprenorphine decreases full mu agonist opioid’s effectiveness, many found the addition of full mu agonists in the perioperative setting to be beneficial for buprenorphine-maintained patients. Buprenorphine’s long half-life, high opioid receptor affinity, partial agonist activity, and slow dissociation from the mu receptor may reduce analgesic effectiveness of full mu opioid agonists; however, the data does not support the commonly held belief that high dose BMT will interfere with the activity of full mu agonist opioids given for the relief of postoperative pain.⁶ Morphine has been shown to be an effective breakthrough medication to control postoperative pain in buprenorphine-maintained patients.¹¹ In a retrospective cohort study, Macintyre et al⁶ confirmed BMT patients who were not given buprenorphine the day after surgery had significantly higher (P=.02) PCA morphine equivalent requirements in the first 24 hours after surgery compared with those who were given their usual dose of buprenorphine. In another uncontrolled comparison of BMT and MMT groups, researchers¹² found that the first 24 hour postoperative PCA opioid requirements were lower for BMT and MMT groups when maintenance drugs were continued compared with BMT and MMT groups whose maintenance drugs had been ceased perioperatively.

Despite the fact that one report⁶ showed a reduction in whole brain mu receptor availability with high doses of buprenorphine, several studies demonstrated that there is no ceiling effect for the analgesic properties of buprenorphine, only for an opioid’s euphoric effects and respiratory depression. It has been shown that buprenorphine attenuates the effects of additional opioid agonists rather than exert an absolute ceiling effect, and this minimizes euphoric properties of concurrently administered opioids and discourages the likelihood of ongoing opioid abuse.² Macintyre et al⁶ also revealed that PCA opioid requirements were lower when BMT was continued after surgery, implying that buprenorphine may still have analgesic effects. Walsh et al¹³ documented no ceiling effect for analgesia in patients that received sublingual buprenorphine up to 32 mg. As there are no additional opioid effects with escalating doses, this property limits abuse potential and minimizes respiratory depression with high doses.² In a study of 20 volunteers, Dahan et al¹⁴ confirmed buprenorphine’s ceiling effect on respiratory depression, but not on its analgesic effects.

As buprenorphine demonstrates a ceiling effect for respiratory depression, it is safe for outpatient use in high doses; however, when used in conjunction with sedatives, a synergistic effect in respiratory depression may occur. One case report⁸ verified that a high daily dose of buprenorphine (72 mg) was safely used as an outpatient dose, though no other respiratory depressants were used. Combining benzodiazepines with buprenorphine can exert a synergistic effect on the central nervous system resulting in sedation and respiratory depression.¹¹ Deaths from buprenorphine have been reported, but it has been suggested that these deaths predominantly occurred as a result of prolonged respiratory depression when administered with sedatives, particularly benzodiazepines.²

There is no consensus on recommendations regarding acute pain management for buprenorphine-maintained patients presenting to the perioperative setting and more research is needed. Some articles^2,5,11 recommend the cessation of buprenorphine preoperatively and conversion to a full opioid agonist throughout the perioperative period. Conversely, others^1,2,5,8 demonstrate successful pain management in the acute pain setting with divided daily and/or additional doses of buprenorphine. The majority of researchers,^{2,3,5,9,11,15} however, support the continuation of usual buprenorphine maintenance therapy with the addition of full mu agonist opioid analgesics for effective perioperative pain control. There are no recommendations based on high level evidence,¹⁵ and data is sparse regarding the best method of treatment for pain in the opioid-dependent population.⁵ Regardless of point of view, most studies agree that additional research regarding acute pain management for patients taking chronic buprenorphine is urgently needed.^5,10,11

DISCUSSION

It is clear that buprenorphine is a better alternative than methadone for the treatment of opioid dependence. Associated with less respiratory depression and a lower abuse profile, buprenorphine is a safer medication than methadone and can be used without difficulty in outpatient therapy. With a long half-life and slow dissociation time, buprenorphine can also be dosed less frequently. Buprenorphine has also been known to cause less side effects than methadone. All of these features can increase adherence to opioid replacement therapy by allowing the opioid-dependent patient a less restrictive lifestyle.

There is a great deal of uncertainty regarding the best method for treating acute surgical pain in patients taking chronic buprenorphine. There are multiple recommendations regarding perioperative pain management and BMT; however, most methods are developed from the results of uncontrolled studies with very small sampling sizes. Consequently, few are able to establish actual significance in their findings. Without concrete evidence, concise standard recommendations are difficult to establish.

CONCLUSION

Based on the literature, the continuation of BMT during the perioperative period with the addition of short acting full mu opioids and/or additional buprenorphine doses is the best approach to treating acute surgical pain.

For future research, more controlled studies with larger sample sizes are needed in order to confirm the best method of acute pain management in the surgical setting for patient’s taking chronic buprenorphine.

References

1. Wasson M, Beirne O. Buprenorphine therapy: an increasing challenge in oral and maxillofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;(2):142. Available from: Academic OneFile, Ipswich, MA. Accessed June 3, 2014.

2. Roberts D, Meyer-Witting M. High-dose buprenorphine: perioperative precautions and management strategies. Anaesth Intensive Care. February 2005;33(1):17-25. Available from: MEDLINE, Ipswich, MA. Accessed June 10, 2014.

3. Bryson E, Lipson S, Gevirtz C. Anesthesia for Patients on Buprenorphine. Anesthesiol Clin. January 1, 2010;28(Perioperative Pharmacotherapy):611-617. Available from: ScienceDirect, Ipswich, MA. Accessed June 3, 2014.

4. Koppert W, Ihmsen H, Korber N, et al. Different profiles of buprenorphineinduced analgesia and antihyperalgesia in a human pain model. Pain 2005;118(1–2):15–22. Cited by: Vadivelu N, Anwar M. Buprenorphine in Postoperative Pain Management. Anesthesiol Clin. January 1, 2010;28(Perioperative Pharmacotherapy):601-609. Available from: ScienceDirect, Ipswich, MA. Accessed June 3, 2014.
5. Vadivelu N, Mitra S, Kaye A, Urman R. Perioperative analgesia and challenges in the drug-addicted and drug-dependent patient. Best Pract Res Clin Anaesthesiol. March 2014;28(1):91. Available from: Supplemental Index, Ipswich, MA. Accessed June 10, 2014.
6. Macintyre P, Russell R, Usher K, Gaughwin M, Huxtable C. Pain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy. Anaesth Intensive Care. March 2013;41(2):222-230. Available from: Academic Search Premier, Ipswich, MA. Accessed June 3, 2014.

7. Kornfield H, Manfredi L. Effectiveness of full agonist opioids in patients stabilized on buprenorphine undergoing major surgery: a case series. Am J Ther 2010;17:523-528. Cited by: Huxtable C, Roberts L, Somogyi A, Macintyre P. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care. September 2011;39(5):804-823. Available from: Academic Search Premier, Ipswich, MA. Accessed June 3, 2014.

8. Book S, Myrick H, Malcolm R, Strain E. Buprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient. Am J Psychiatry. June 2007;164(6)Available from: PsycINFO, Ipswich, MA. Accessed June 3, 2014.

9. Jones H, Johnson R, Milio L. Post-cesarean pain management of patients maintained on methadone or buprenorphine. Am J Addict. May 2006;15(3):258-259. Available from: MEDLINE, Ipswich, MA. Accessed June 3, 2014.

10. Chern S, Isserman R, Chen L, Ashburn M, Liu R. Perioperative Pain Management for Patients on Chronic Buprenorphine: A Case Report. J Anesth Clin Res. October 2012;3(10):1. Available from: Supplemental Index, Ipswich, MA. Accessed June 3, 2014.

11. Vadivelu N, Anwar M. Buprenorphine in Postoperative Pain Management. Anesthesiol Clin. January 1, 2010;28(Perioperative Pharmacotherapy):601-609. Available from: ScienceDirect, Ipswich, MA. Accessed June 3, 2014.

12. Russell R, Usher K, Macintyre PE. A comparison of postoperative opioid requirements and effectiveness in methadone- and buprenorphine-maintained patients. Anaesth Intensive Care. 2011;39:726-727. Cited by: Huxtable C, Roberts L, Somogyi A, Macintyre P. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care. September 2011;39(5):804-823. Available from: Academic Search Premier, Ipswich, MA. Accessed June 3, 2014.

13. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5):569–80. Cited by: Vadivelu N, Anwar M. Buprenorphine in Postoperative Pain Management. Anesthesiol Clin. January 1, 2010;28(Perioperative Pharmacotherapy):601-609. Available from: ScienceDirect, Ipswich, MA. Accessed June 3, 2014.

14. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006;96(5):627–32. Cited by: Vadivelu N, Anwar M. Buprenorphine in Postoperative Pain Management. Anesthesiol Clin. January 1, 2010;28(Perioperative Pharmacotherapy):601-609. Available from: ScienceDirect, Ipswich, MA. Accessed June 3, 2014.

15. Huxtable C, Roberts L, Somogyi A, Macintyre P. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care. September 2011;39(5):804-823. Available from: Academic Search Premier, Ipswich, MA. Accessed June 3, 2014.