Buprenorphine–naloxone (bup/nal in 4:1 ratio; Suboxone®; Reckitt Benckiser Pharmaceuticals Incorporation, Richmond, VA) is approved by the Food and Drug Administration for outpatient office-based addiction treatment. In the past few years, bup/nal has been increasingly prescribed off-label for chronic pain management. The current data suggest that bup/nal may provide pain relief in patients with chronic pain with opioid dependence or addiction. However, the unique pharmacological profile of bup/nal confers it to be a weak analgesic that is unlikely to provide adequate pain relief for patients without opioid dependence or addiction. Possible mechanisms of pain relief by bup/nal therapy in opioid-dependent patients with chronic pain may include reversal of opioid-induced hyperalgesia and improvement in opioid tolerance and addiction. Additional studies are needed to assess the implication of bup/nal therapy in clinical anesthesia and perioperative pain management.

CHRONIC pain lasting more than 3 to 6 months can affect anyone at any stage in life.1  In 2010, 31% of the American population experienced chronic pain.2  It is one of the most frequent reasons to seek medical care and a major public health problem for both individuals and the society. For centuries, opioids have been used for pain management and regarded as among the most powerful drugs for the treatment of chronic pain. When properly managed, opioid therapy is considered to improve patients’ quality of life, decrease healthcare costs, and promote work productivity.

The increasing number of patients searching for pain relief during the last several decades has led pharmaceutical companies to develop a plethora of opioid medications. Unfortunately, this increase in the number of opioid medications and dispensing is correlated with an increase in opioid abuse.3,4  According to a recent report, approximately 21 million people in the United States aged 12 and older have used prescription drugs for nonmedical reasons at least once in their lifetimes.5  The increase in the nonmedical use of opioids is paralleled by the steady increase in the number of deaths from unintentional opioid overdoses. Since 2003, more deaths have been associated with opioid overdose than cocaine or heroin use combined.6  In addition to the known side effects associated with the use of opioid analgesics, the nonmedical use of prescription opioids has made it much more difficult to achieve the goal of alleviating pain with opioid therapy without causing significant adverse consequences. This issue is further complicated by managing patients with both chronic pain and opioid dependence or addiction.

Buprenorphine–naloxone (bup/nal; Suboxone® [Reckitt Benckiser Pharmaceuticals Incorporation, Richmond, VA]) is a semisynthetic opioid. Although developed as an analgesic, bup/nal was popularized for its effectiveness in opioid-replacement therapy. With the increasing challenge of managing pain in opioid-dependent patients, bup/nal has been prescribed off-label for the treatment of chronic pain, whereas a consensus is yet to be reached with regard to its effectiveness. To assess the effectiveness of bup/nal therapy, it would be important to determine the effectiveness of bup/nal in at least three patient populations who (1) have opioid addiction but without chronic pain; (2) have chronic pain on high-dose opioids; and (3) are dependent on or addicted to opioids with coexisting chronic pain. In this article, we will (1) examine the effectiveness of bup/nal in these patient populations, (2) compare the effectiveness of bup/nal with that of methadone in pain management, (3) discuss implications of bup/nal therapy in clinical anesthesia and perioperative pain management, and (4) examine possible mechanisms of bup/nal therapy in pain management.

We aimed for an integrative summary of the current knowledge on the effectiveness of using bup/nal for pain management. A computerized literature search in PubMed and Google Scholar was conducted between June 10, 2013 and August 2, 2013, which included the available literature up to that point. The following keywords and their combinations were used in both searches: suboxone, buprenorphine–naloxone, buprenorphine, naloxone, subutex, chronic pain, pain management, opioid dependent, office-based addiction, methadone, pharmacology, opioid-induced hyperalgesia (OIH), opioid naive, and buprenorphine history. This search included review articles, prospective and retrospective clinical studies, editorials, and comments. We also searched for relevant articles by using those keywords in the reference lists from the retrieved journals. No time restraint was placed on the literature search, but the search results indicate that all of the clinical trials relating bup/nal to pain management were conducted from 2002 and onwards. Studies were included if they specify buprenorphine or bup/nal as the primary pharmacological agent used for either opioid management or pain management. Studies that compared bup/nal therapy to other opioids in terms of pain management or opioid management were also included. In analyzing the published articles and organizing this review, we recognized that the literature pool on this topic is still relatively small that may not be appropriate for us to construct a traditional systematic review with the rating on the published articles. Instead, we consider this article as a topical review with a combination of up-to-date references and comments on the relevance to the topic under review. These comments are included in the main text and in four tables.

### Historic Perspectives

After decades of research and many failed attempts, Reckitt & Colman Research Lab (now Reckitt Benckiser Pharmaceuticals) in England synthesized buprenorphine in 1966. With high enthusiasm for the drug, the intravenous form of buprenorphine became available in 1978. Soon after, in 1982, a sublingual version of buprenorphine became available for analgesia. In 1985, buprenorphine was introduced into the United States as an opioid analgesic.7  To date, buprenorphine is formulated in two forms. The initial form contains only buprenorphine (e.g., Subutex®; Reckitt Benckiser Pharmaceuticals Incorporation). Similar to other opioids, buprenorphine has the potential to be intravenously abused as shown by an increasing record of abuse in many countries.8  To address this issue, naloxone (an opioid receptor antagonist) was added to buprenorphine and this buprenorphine–naloxone (bup/nal) combination drug was trademarked as Suboxone®. Although Subutex® and Suboxone® both contain buprenorphine as its main ingredient, the addition of naloxone to buprenorphine pharmacologically distinguishes bup/nal from buprenorphine due to the opioid-antagonizing effect of naloxone.

In 2000, the U.S. Drug Addiction Treatment Act made it legal to prescribe schedule III, IV, V drugs to manage addiction and placed the limit of the number of patients on maintenance therapy to 100 patients under a single physician.* In 2002, the U.S. Food and Drug Administration approved bup/nal for office-based addiction treatment by categorizing it as a schedule III drug.7  Later in 2007, the World Health Organization recognized buprenorphine and bup/nal as a treatment for opioid dependence by including both drugs in the 15th World Health Organization Model List of Essential Medicines, and both drugs have been on the list ever since.§ By 2011, there had been 7.69 million buprenorphine-related prescriptions dispensed in the United States alone, with the majority of it being bup/nal.

### Pharmacological Profile of Bup/Nal

#### Characteristics of Buprenorphine

Buprenorphine is a semisynthetic opioid as a derivative of thebaine, a naturally occurring opium alkaloid of Papaver somniferum. It has several interesting pharmacological characteristics that account for its unique mechanism of action. First, buprenorphine has a high binding affinity to the μ-opioid receptor, effectively competing with other opioids that bind to the same receptor (fig. 1). Second, buprenorphine functions as a partial μ-opioid receptor agonist (fig. 1). When buprenorphine binds to the μ-opioid receptor, it mimics the pharmacological effect of an opioid but to a much lesser extent, thus preventing opioid withdrawal symptoms. Third, buprenorphine has a slow rate of dissociation from the μ-opioid receptor, producing a prolonged duration of action as compared with other opioids.9,10  Fourth, buprenorphine is also a full κ-opioid receptor antagonist. Activation of the κ-opioid receptor contributes to the opioid’s dysphoric and psychotomimetic effects, which could be diminished by buprenorphine.11–13  Fifth, buprenorphine has a large volume of distribution and is highly protein bound (96%), primarily to α- and β-globin.14  Buprenorphine reaches its peak plasma concentration 90 min after administration and is extensively metabolized through 14-N-dealkylation by the hepatic CYP3A4 (primary pathway), CYP2C8, and CYP2C9 system to norbuprenorphine. Both buprenorphine and norbuprenorphine can then undergo glucuronidation by the uridine 5’-diphospho glucuronosyl transferases to form conjugated byproducts.15,16 # These glucuroconjugated metabolites are then eliminated mainly in feces by biliary excretion 4 to 6 days after administration with minimal urinary excretion.16  Early studies have shown that in mouse, buprenorphine can be 25 to 40 times more potent than morphine if given a parenteral injection and 7 to 10 times more potent after an oral administration and is longer acting.9,17

Fig. 1.

Schematic illustration of the effect of buprenorphine as a partial μ-opioid receptor agonist.

Fig. 1.

Schematic illustration of the effect of buprenorphine as a partial μ-opioid receptor agonist.

#### Characteristics of Naloxone

Naloxone is a short-acting, broad opioid receptor antagonist. It binds to opioid receptors with high affinity and becomes a competitive antagonist of opioid receptors (fig. 2). When administered at low doses, naloxone can reverse opioid side effects such as respiratory depression, sedation, and hypotension without significantly reversing analgesia. At high doses, however, naloxone can block opioid analgesia causing precipitated opioid withdrawal.18  Naloxone is approximately 45% protein bound, primarily to albumin. It is rapidly metabolized by glucuronidation to naloxone-3-glucuronide in the liver and is primarily excreted in urine.**

Fig. 2.

Schematic illustration of the antagonizing effect of naloxone, an element in buprenorphine–naloxone, on μ-opioid receptors.

Fig. 2.

Schematic illustration of the antagonizing effect of naloxone, an element in buprenorphine–naloxone, on μ-opioid receptors.

#### Characteristics of Bup/Nal

Bup/nal is a sublingual combination tablet composed of buprenorphine and naloxone in a fixed 4:1 ratio. The fixed ratio was based on the need to maintain the therapeutic effect of buprenorphine while minimizing the antagonist effect of naloxone. Naloxone has no major clinical effect when administered sublingually and has a minimal impact on the pharmacological effect of buprenorphine for two reasons. First, there is a substantial difference in sublingual bioavailability of these two drugs. When administered sublingually, the bioavailability of buprenorphine (40%) is much higher than that of naloxone (10%) so that buprenorphine will exert the predominate effect.19  Second, buprenorphine has 10 times longer duration of action (966 min) than that of naloxone (105 min) in the intravenous form.9,14,17  As such, adding naloxone to buprenorphine could prevent intravenous abuse of buprenorphine because the bioavailability of naloxone increases when bup/nal is injected intravenously and its antagonist effect will render this combination drug undesirable for intravenous drug users.14

Despite a favorable pharmacological profile of bup/nal, bup/nal does have a number of adverse effects mainly through drug–drug interactions. Similar to other opioids, some typical side effects of bup/nal include nausea, dizziness, vomiting, and other symptoms. However, because buprenorphine is metabolized by the CYP3A4 system, it interacts with many drugs that are also cleared through this same P450 system. A serious and fatal drug interaction can occur in individuals who are concurrently taking buprenorphine with benzodiazepines (e.g., diazepam or flunitrazepam). Benzodiazepines are also cleared by the hepatic P450 system and can lead to accumulation of drug metabolites. Other drugs that can affect the P450 system include antifungals (e.g., fluconazole), antibiotics (e.g., clarithromycin), and antidepressants (e.g., fluoxetine) and should be avoided these drugs when taking buprenorphine.

### Bup/Nal versus Buprenorphine Alone

A main pharmacological difference between buprenorphine and bup/nal is that the latter has naloxone added to buprenorphine. Studies have shown that the pharmacological effect of buprenorphine seems to be different in the form of bup/nal. For example, buprenorphine has a slightly higher sublingual bioavailability in bup/nal compared with the sublingual bioavailability in buprenorphine alone.20  The addition of naloxone might also attenuate the acute effect of buprenorphine despite a low sublingual bioavailability of naloxone.21  Moreover, when switched from buprenorphine to bup/nal in opioid-dependent patients, 50% of subjects in one study experienced adverse reactions that were absent before the switch, suggesting that these two drugs could have different pharmacodynamic profiles.22  In another study, approximately 80% of opioid-dependent subjects who switched from buprenorphine to bup/nal had a “bad” experience and fewer than 20% of them felt that the two drugs were similar.23  In yet another study, 54% of opioid-dependent subjects preferred the tablet size, taste, and sublingual dissociation time of bup/nal as compared with buprenorphine.24  Collectively, these studies suggest that adding naloxone to buprenorphine may have pharmacologically transformed buprenorphine to be distinctly different from buprenorphine as a mono drug.

### Bup/Nal for Outpatient Office-based Opioid Addiction Treatment

To date, a number of studies have focused on the efficacy of bup/nal as an outpatient office-based treatment for opioid addiction (table 1). It has been shown that patients addicted to opioids can be safely treated in a primary care setting with limited resources and that the success rates were similar to those from specialized treatment centers using methadone.26  Furthermore, there are potential economic advantages for treating clinically stable opioid-dependent patients with office-based bup/nal therapy. In a study that analyzed the cost effectiveness of treating patients with bup/nal (compared with no treatment) by using the monthly cost of bup/nal in 2010 against the improvement in the quality of life of the patient, they found that bup/nal maintenance therapy has a cost-effective ratio of $35,100/Quality-Adjusted Life Years and has 64% chance of being below the$100,000/Quality-Adjusted Life Years threshold as compared with no treatment.27  The ratio shows the cost of bup/nal therapy to patients for every year of improved quality of life from the therapy. Current interventions with a cost-effectiveness ratio below \$100,000/Quality-Adjusted Life Years are considered to be a good value in the United States.27  In addition to being cost effective, patients are generally satisfied with bup/nal (rating 4.4 of 5) and those (40%) who were abstinent from illicit drug use in the first 6 months remained in maintenance treatment for an additional 2 yr.28,29  Patients under bup/nal therapy were more likely to report abstinence (as compared with those not on bup/nal therapy), be involved in a 12-step recovery, be employed, and have improved psychosocial functional status (e.g., “less likely to be unhappy,” “have negative personality changes,” or “do regretful things, and hurt family”).30  Collectively, these studies demonstrate the efficacy of bup/nal in office-based treatment for opioid addiction.

Table 1.

Clinical Data on Bup/Nal as an Outpatient Office-based Addiction Treatment

### Bup/Nal as an Opioid Maintenance Therapy

In recent years, the increasing use of prescription opioids has been associated with a steady increase in prescription drug abuse and opioid-related death.3,4  The unique pharmacological profile of bup/nal as a partial μ-agonist and full κ-antagonist in a fixed ratio with naloxone suggests that it could be used in opioid maintenance therapy. Maintenance therapy is a primary pharmacological approach to managing opioid dependence, which involves “replacement of abused opioids with medically prescribed opioids that are slow in onset, long acting, and less likely to be abused.”31  A number of studies have shown potential benefits of using bup/nal in patients who are dependent on opioids but without chronic pain (table 1). In a clinical trial, subjects on buprenorphine or bup/nal had more negative urinary samples for opioids, 40% less craving for opioids, and improved overall health status as compared with those on placebo.32  However, it remains unclear as to whether bup/nal maintenance therapy is superior to methadone maintenance therapy, which has been the standard of care for opioid-addicted patients. Some studies have shown that bup/nal is as effective as methadone in producing negative urine samples for opioids and can be used as an alternative to methadone maintenance therapy.33,34  At least one study suggests that bup/nal might be even more effective than methadone in reducing opioid consumption and preserving cognitive function.35  Other studies suggest that methadone is more effective than bup/nal in reducing opioid use and retaining patients in the maintenance therapy.36

Several properties of bup/nal as a maintenance therapy are related to its unique pharmacologic profile. For example, the partial agonist activity of bup/nal can limit its therapeutic efficacy to a daily dose of 24 or 32 mg, which is equivalent to 60 to 70 mg methadone per day. Because many opioid-addicted patients were often placed on a much higher methadone maintenance dose (usually 80 to 150 mg of methadone per day), bup/nal might not be as effective in such patients.37  Nonetheless, with a lower abuse potential due to the addition of naloxone, a safety profile due to its ceiling effects and fewer withdrawal symptoms upon discontinuation and fewer respiratory depression complications than other opioids, bup/nal may be considered as a first-line medication for those who just begin opioid-dependence treatments.12,17

### Rationales for Using Bup/Nal in Pain Management

In 2000, the American Pain Society and the American Academy of Pain Medicine published statements supporting the use of opioid therapy in patients with chronic pain. However, opioid medications are addictive and can cause adverse social, financial, mental, and economic consequences. Studies have shown that up to 45% of patients with chronic pain on opioid therapy reported aberrant drug-related behaviors. These behaviors include the use of alternative routes of administration of oral formulations, concurrent use of alcohol or illicit drugs, and the repeated usage of opioid therapy despite adverse effects.38  Given that buprenorphine is regarded as an analgesic with a low addictive potential, sublingual buprenorphine and bup/nal have become increasingly prescribed off-label for the treatment of chronic pain based on the following considerations.39  First, opioid dependence and addiction is an issue in many patients with chronic pain on opioid therapy. Patients with chronic pain are often prescribed with opioid medications that are subject to addiction and abuse. Second, patients on high-dose opioids often require alternative treatment for pain relief due to opioid tolerance and/or OIH.40,41  Third, for those patients on high-dose opioids for chronic pain management, bup/nal could help taper these patients off, or lower, their dose of opioids. Despite these compelling reasons, a consensus is yet to be reached regarding the effectiveness of bup/nal therapy for patients with chronic pain as discussed in the following paragraphs.

### Bup/Nal Therapy in Patients with Pain without Opioid Dependence

To our knowledge, there are currently no published studies that show the effectiveness of bup/nal for pain relief in non–opioid-dependent patients with chronic pain. This may not be surprising given that buprenorphine is a weak analgesic. In low doses, buprenorphine can only partially activate the μ-opioid receptor. In moderate doses, the buprenorphine’s opioid agonist effect reaches a plateau (ceiling) such that any further dose increase is unlikely to enhance analgesia. In high doses, buprenorphine functions as an opioid antagonist to further limit its analgesic effect.42  Thus, the weak analgesic effect of buprenorphine in the form of bup/nal is unlikely to provide adequate pain relief for patients without opioid dependence or addiction.

### Bup/Nal Therapy in Patients with Pain with Opioid Dependence

Patients with chronic pain with a coexisting substance abuse disorder are among the most challenging patients to manage. Effective pain management in this patient population is often complicated by opioid tolerance including cross-tolerance to various opioids and OIH. Bup/nal may have advantages over other opioids in this patient population because of its low addictive potential and partial μ-opioid receptor agonist activities. Indeed, an increasing number of studies support the concept of using bup/nal in opioid-dependent patients with chronic pain (table 2).

Table 2.

Clinical Data on Bup/Nal Therapy in Patients with Pain with Opioid Dependence

In one study, patients with chronic pain who converted from a full-agonist opioid therapy to a bup/nal therapy experienced a 2.3-point pain reduction (0 to 10 pain scale) within 60 days of the switch.43  A retrospective chart review study conducted in a primary care setting also found that most patients with both nonmalignant chronic pain and opioid dependence who stayed on a bup/nal therapy showed a reduced pain level and required lower doses of bup/nal over time, and those who completed a bup/nal therapy were no longer taking any opioids.44  Additional evidence is provided by several randomized clinical trials showing that (1) patients with chronic pain with opioid dependence experienced a 12.7% reduction in pain with a bup/nal therapy36  and (2) bup/nal therapy reduced pain, opioid withdrawal symptoms, and opioid abuse in patients with chronic pain who were abusing oxycodone.45  Collectively, the current data appear to support a role for bup/nal therapy in patients with chronic pain with opioid dependence or addiction.

### Possible Mechanisms of Bup/Nal Therapy in Patients with Pain with Opioid Dependence

Although clinical data support a role of bup/nal therapy in patients with chronic pain with opioid dependence, the cause of pain relief in this patient population remains unclear. To date, most studies have focused on examining the effectiveness of bup/nal in pain management, but few have explored its underlying mechanisms. Does pain relief by bup/nal in this patient population result from reversal of OIH and/or opioid tolerance that are often associated with high-dose opioid therapy?40,41  Does improvement of opioid dependence or addiction itself after bup/nal therapy lead to better pain relief in this patient population?

Several recent studies may shed some light on the possible mechanism of pain relief by bup/nal therapy. It has been shown that buprenorphine is an antinociceptive, although weak, by activation of the μ-opioid receptor.9,46  In human subjects, buprenorphine exerts an antihyperalgesic effect and this effect has a longer half time than its analgesic effects.47  Buprenorphine has been shown to reverse hyperalgesia induced by opioids through “buprenorphine-induced antinociception.”47,48  Moreover, buprenorphine is a κ-receptor antagonist and can compete with the effect of spinal dynorphin, an endogenous κ-receptor agonist. Because spinal dynorphin is increased after opioid exposure and contributes to OIH,49  this competitive effect of buprenorphine on the κ-receptor binding site may decrease the effect of spinal dynorphin resulting in the decreased OIH.50  Thus, reversing OIH might be a potential mechanism by which bup/nal therapy produces pain relief in patients with chronic pain with opioid dependence. Future studies are expected to examine whether pain relief by bup/nal in this patient population could also result from its effect on opioid tolerance and addiction.

### Buprenorphine Alone in Patients with Pain without Opioid Dependence

Buprenorphine is often considered a second-line therapy for pain management because of its weak partial agonist activity. Most studies using buprenorphine alone have focused on the transdermal administration because of its high lipophilic properties. To date, there has not been a consensus as to whether buprenorphine alone would be an effective treatment in opioid-naive patients (table 3). One study showed that transdermal buprenorphine significantly alleviated chronic back pain in opioid-naive patients. But this decrease in pain became statistically nonsignificant when those patients who discontinued treatment were included as nonresponders.51  Similarly, other studies have shown that transdermal buprenorphine was effective in reducing nonmalignant persistent pain, but it was only effective in 11% of the study subjects.52  In that same study, 41% of patients on transdermal buprenorphine had discontinued the treatment due to unacceptable side effects or inadequate pain relief.52  Other studies showed that patients on transdermal buprenorphine patches had improvement in their quality of life but with only moderate pain reduction.53  Another study found similar results where buprenorphine was able to improve the overall wellbeing of patients suffering from osteoarthritis by improving sleep and movement abilities, but it did not reduce pain for these patients.54  However, other studies showed that buprenorphine was able to alleviate pain in patients with cancer and can improve quality of life in these patients.55  Overall, the exact role of buprenorphine in patients with chronic pain without opioid dependence remains to be investigated in future studies.

Table 3.

Clinical Data on Buprenorphine in Patients with Pain without Opioid Dependence

### Buprenorphine Alone in Patients with Pain with Opioid Dependence

Similar to bup/nal, buprenorphine alone has been shown to alleviate pain in opioid-dependent patients (table 4). Patients treated with transdermal buprenorphine showed good or complete pain relief, improved duration of sleep, improved quality of life, and reduced need for additional sublingual buprenorphine.56,57  A postmarketing surveillance study produced similar results on the effectiveness of transdermal buprenorphine in opioid-dependent patients with chronic pain who had inadequate analgesia from other opioids, showing that approximately 80% of the participants reported good pain relief and 70% of them moved onto a bup/nal therapy.58  In addition, clinical studies, including a randomized clinical trial, have shown that substantial pain relief (66 to 82% pain reduction) can also be achieved in patients with chronic pain who were placed on sublingual buprenorphine after failed other opioid therapies.59,60

Table 4.

Clinical Data on Buprenorphine in Patients with Pain with Opioid Dependence

### Bup/Nal versus Methadone in Pain Management

Methadone is a racemic mixture of two stereoisomers (l- and d-methadone) with l-methadone being 8 to 50 times more potent than d-methadone and pharmacologically more active.61,62  It is a full agonist at the μ-opioid receptor and an antagonist at the glutamatergic N-methyl-d-aspartate receptor. The N-methyl-d-aspartate receptor plays an important role in neuronal excitation, memory, opioid tolerance, and OIH.40,41  Acting as an N-methyl-d-aspartate receptor antagonist may be one mechanism by which methadone is effective in the treatment of neuropathic pain.63  Methadone also inhibits reuptake of serotonin and norepinephrine, making it useful for the treatment of other pain conditions as well.64  It has high oral and rectal absorption, high liposolubility, no known active metabolites, high potency, low cost, and longer administration intervals as compared with many μ-opioid receptor agonists.65  Moreover, methadone has the potential to control pain that fails to respond to other opioids because of its incomplete cross-tolerance with other opioid analgesics.65

However, methadone has a number of adverse pharmacological properties. It has a long and unpredictable half-life (13 to 58 h) although, after oral administration, it can be detected in the plasma in 30 min. It has a bioavailability of approximately 80%, ranging from 41 to 95%, such that individual serum levels can vary greatly.61,66  Methadone also interacts frequently with other medications and has significant systemic toxicity to the heart (e.g., prolonged QTc intervals).65  Methadone toxicity, particularly when used with benzodiazepines, can cause hypoxia and severe pulmonary edema, and can eventually lead to death.67  As such, methadone could be rather difficult to manage in pain treatment and requires individualized dosing with proper monitoring for side effects.65

To date, it remains controversial as to whether methadone should be preferentially used, as compared with bup/nal, for opioid-dependent patients with coexisting chronic pain. A randomized, clinical trial comparing bup/nal to methadone in opioid-dependent patients with pain found that both the treatment retention rate and the analgesic effect did not significantly differ between these two drugs, but methadone was superior to bup/nal in reducing illicit opioid use.36  In this same study, however, subjects receiving bup/nal showed better improvement in mood, energy, personality, and the psychological component of chronic pain as compared with those on methadone.36

Of significance to note is that bup/nal therapy is likely to be superior to methadone in at least two patient populations. In pregnant women with opioid dependence, bup/nal has been shown to be more beneficial than methadone for both opioid-dependent mothers and new born babies (fewer neonatal abstinence symptoms and higher birth weight).68  Although methadone is currently the only recommended medication in the Unites States for pain management in pregnant women with opioid dependence, there has been increasing support to add bup/nal to the list. In patients with renal failure, bup/nal is also superior to methadone because the former is metabolized through the hepatic CYP3A4 system and excreted through feces.69  Although methadone is metabolized by the hepatic CYP3A4 and CYP2B6 system, it is eliminated through the kidney and feces (the enterohepatic route). When the urine pH is below 6, as much as 30% of the methadone metabolite is eliminated through the kidney.62,66  Therefore, a longer duration of action of methadone in patients with renal failure may lead to drug accumulation and dangerous side effects.70

### Implications of Bup/Nal in Clinical Anesthesia and Perioperative Pain Management

Implications of bup/nal therapy in clinical anesthesia and perioperative pain management remain unclear. However, several issues warrant further examination with regard to intra- and perioperative management of patients on a bup/nal maintenance therapy. First, because buprenorphine is a partial opioid agonist with a high affinity for μ-opioid receptors, it can block other opioids from activating the same receptors. As such, patients on bup/nal therapy would be expected to require a higher dose of opioid during the intra- and perioperative period.71  Second, a standard opioid-based anesthesia plan may be insufficient in patients on bup/nal therapy and other agents would be required to produce adequate analgesia. Third, ongoing bup/nal therapy may need to be replaced with other opioids several days (3 to 7 days) before anesthesia to ensure proper intra- and postoperative pain management. Fourth, if bup/nal therapy is replaced by other opioids preoperatively, reinstatement of bup/nal therapy postoperatively should be carefully managed to maintain adequate pain relief. Fifth, it would be of interest to determine whether buprenorphine, alone or with naloxone, would induce withdrawal symptoms in patients on high-dose opioids. To date, there is limited information regarding the impact of buprenorphine on clinical anesthesia.72  Further studies will be needed to formulate the best clinical management plan in patients on bup/nal therapy during the intra- and perioperative period.

As summarized in figure 3, the current data suggest that bup/nal can be used as an effective outpatient office-based treatment for opioid addiction. It can also be used, as an alternative to methadone, in opioid-replacement therapy to help opioid-dependent patients reduce opioid use. Bup/nal, as a weak analgesic, seems to be not as effective in non–opioid-dependent patients with chronic pain. However, it has been successfully used for pain relief in opioid-dependent patients with chronic pain possibly due to the reversal of OIH. Future studies should address the implications of bup/nal therapy in clinical anesthesia and perioperative pain management.

Fig. 3.

A flowchart illustrating the clinical effect of buprenorphine–naloxone (bup/nal) on various categories of patients with chronic pain with or without opioid dependence or addiction. OIH = opioid-induced hyperalgesia.

Fig. 3.

A flowchart illustrating the clinical effect of buprenorphine–naloxone (bup/nal) on various categories of patients with chronic pain with or without opioid dependence or addiction. OIH = opioid-induced hyperalgesia.

Supported by Foundation for Anesthesia Education and Research (Rochester, Minnesota) Summer Research Grant (to Kelly Yan Chen) and National Institutes of Health (Bethesda, Maryland) R01 grants DE18538, DE 22901, DA36564 (to Jianren Mao and Lucy Chen).

The authors declare no competing interests.

*

U.S. Department of Health and Human Services. Available at: http://buprenorphine.samhsa.gov/data.html. Accessed August 1, 2013.

World Health Organization: WHO Model List of Essential Medicines. 2007. Available at: http://whqlibdoc.who.int/hq/2007/a95075_eng.pdf. Accessed July 1, 2013.

World Health Organization: WHO Model List of Essential Medicine. 2010. Available at: http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf. Accessed July 1, 2013.

§

World Health Organization: WHO Model List of Essential Medicine. 2011. Available at: http://whqlibdoc.who.int/hq/2010/a95060_eng.pdf. Accessed July 1, 2013.

#

European Medicine Agency: Summary of Product Characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000697/WC500058505.pdf. Accessed July 1, 2013.

**

Reckitt Benckiser Pharmaceuticals Incorporation. Available at: http://www.suboxone.com/pdfs/suboxonePI.pdf. Accessed July 1, 2013.

††

Drug and Treatment Act of 2000. Available at: http://buprenorphine.samhsa.gov/waiver_qualifications.html. Accessed August 1, 2013.

1.
Toblin
RL
,
Mack
KA
,
Perveen
G
,
Paulozzi
LJ
:
A population-based survey of chronic pain and its treatment with prescription drugs.
Pain
2011
;
152
:
1249
55
2.
Johannes
CB
,
Le
TK
,
Zhou
X
,
Johnston
JA
,
Dworkin
RH
:
The prevalence of chronic pain in United States adults: Results of an Internet-based survey.
J Pain
2010
;
11
:
1230
9
3.
Compton
WM
,
Volkow
ND
:
Major increases in opioid analgesic abuse in the United States: Concerns and strategies.
Drug Alcohol Depend
2006
;
81
:
103
7
4.
Paulozzi
LJ
,
Budnitz
DS
,
Xi
Y
:
Increasing deaths from opioid analgesics in the United States.
Pharmacoepidemiol Drug Saf
2006
;
15
:
618
27
5.
Kroutil
LA
,
Van Brunt
DL
,
Herman-Stahl
MA
,
Heller
DC
,
Bray
RM
,
Penne
MA
:
Nonmedical use of prescription stimulants in the United States.
Drug Alcohol Depend
2006
;
84
:
135
43
6.
Okie
S
:
A flood of opioids, a rising tide of deaths.
N Engl J Med
2010
;
363
:
1981
5
7.
Campbell
ND
,
Lovell
AM
:
The history of the development of buprenorphine as an addiction therapeutic.
2012
;
1248
:
124
39
8.
Yokell
MA
,
Zaller
ND
,
Green
TC
,
Rich
JD
:
Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: An international review.
Curr Drug Abuse Rev
2011
;
4
:
28
41
9.
Cowan
A
,
Lewis
JW
,
Macfarlane
IR
:
Agonist and antagonist properties of buprenorphine, a new antinociceptive agent.
Br J Pharmacol
1977
;
60
:
537
45
10.
Tejwani
GA
,
Rattan
AK
:
The role of spinal opioid receptors in antinociceptive effects produced by intrathecal administration of hydromorphone and buprenorphine in the rat.
Anesth Analg
2002
;
94
:
1542
6
11.
Pfeiffer
A
,
Brantl
V
,
Herz
A
,
Emrich
HM
:
Psychotomimesis mediated by kappa opiate receptors.
Science
1986
;
233
:
774
6
12.
Jones
HE
:
Practical considerations for the clinical use of buprenorphine.
Sci Pract Perspect
2004
;
2
:
4
20
13.
Leander
JD
:
Buprenorphine has potent kappa opioid receptor antagonist activity.
Neuropharmacology
1987
;
26
:
1445
7
14.
Chiang
CN
,
Hawks
RL
:
Pharmacokinetics of the combination tablet of buprenorphine and naloxone.
Drug Alcohol Depend
2003
;
70
(
2 suppl
):
S39
47
15.
Brown
SM
,
Holtzman
M
,
Kim
T
,
Kharasch
ED
:
Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active.
Anesthesiology
2011
;
115
:
1251
60
16.
Cone
EJ
,
Gorodetzky
CW
,
D
,
Buchwald
WF
,
Johnson
RE
:
The metabolism and excretion of buprenorphine in humans.
Drug Metab Dispos
1984
;
12
:
577
81
17.
Jasinski
DR
,
Pevnick
JS
,
Griffith
JD
:
Human pharmacology and abuse potential of the analgesic buprenorphine: A potential agent for treating narcotic addiction.
Arch Gen Psychiatry
1978
;
35
:
501
16
18.
Levine
JD
,
Gordon
NC
,
Fields
HL
:
Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain.
Nature
1979
;
278
:
740
1
19.
Harris
DS
,
Jones
RT
,
Welm
S
,
Upton
RA
,
Lin
E
,
Mendelson
J
:
Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine.
Drug Alcohol Depend
2000
;
61
:
85
94
20.
Strain
EC
,
Moody
DE
,
Stoller
KB
,
Walsh
SL
,
Bigelow
GE
:
Relative bioavailability of different buprenorphine formulations under chronic dosing conditions.
Drug Alcohol Depend
2004
;
74
:
37
43
21.
Weinhold
LL
,
Bigelow
GE
,
Preston
KL
:
Combination of naloxone with buprenorphine in humans.
NIDA Res Monogr
1989
;
95
:
485
22.
Simojoki
K
,
Vorma
H
,
Alho
H
:
A retrospective evaluation of patients switched from buprenorphine (Subutex) to the buprenorphine/naloxone combination (Suboxone).
Subst Abuse Treat Prev Policy
2008
;
3
:
16
23.
Alho
H
,
Sinclair
D
,
Vuori
E
,
Holopainen
A
:
Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users.
Drug Alcohol Depend
2007
;
88
:
75
8
24.
Daulouède
JP
,
Caer
Y
,
Galland
P
,
Villeger
P
,
Brunelle
E
,
Bachellier
J
,
Piquet
JM
,
Harbonnier
J
,
Leglise
Y
,
Courty
P
:
Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: A prospective, multicenter study.
J Subst Abuse Treat
2010
;
38
:
83
9
25.
Judd
LL
:
Effective medical treatment of opiate addiction. National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction.
JAMA
1998
;
280
:
1936
43
26.
Mintzer
IL
,
Eisenberg
M
,
Terra
M
,
MacVane
C
,
Himmelstein
DU
,
Woolhandler
S
:
Treating opioid addiction with buprenorphine-naloxone in community-based primary care settings.
Ann Fam Med
2007
;
5
:
146
50
27.
Schackman
BR
,
Leff
JA
,
Polsky
D
,
Moore
BA
,
Fiellin
DA
:
Cost-effectiveness of long-term outpatient buprenorphine-naloxone treatment for opioid dependence in primary care.
J Gen Intern Med
2012
;
27
:
669
76
28.
Barry
DT
,
Moore
BA
,
Pantalon
MV
,
Chawarski
MC
,
Sullivan
LE
,
O’Connor
PG
,
Schottenfeld
RS
,
Fiellin
DA
:
Patient satisfaction with primary care office-based buprenorphine/naloxone treatment.
J Gen Intern Med
2007
;
22
:
242
5
29.
Fiellin
DA
,
Moore
BA
,
Sullivan
LE
,
Becker
WC
,
Pantalon
MV
,
Chawarski
MC
,
Barry
DT
,
O’Connor
PG
,
Schottenfeld
RS
:
Long-term treatment with buprenorphine/naloxone in primary care: Results at 2–5 years.
2008
;
17
:
116
20
30.
Parran
TV
,
CA
,
Merkin
B
,
Pagano
ME
,
Defranco
R
,
Ionescu
RA
,
Mace
AG
:
Long-term outcomes of office-based buprenorphine/naloxone maintenance therapy.
Drug Alcohol Depend
2010
;
106
:
56
60
31.
Collins
GB
,
McAllister
MS
:
Buprenorphine maintenance: A new treatment for opioid dependence.
Cleve Clin J Med
2007
;
74
:
514
20
32.
Fudala
PJ
,
Bridge
TP
,
Herbert
S
,
Williford
WO
,
Chiang
CN
,
Jones
K
,
Collins
J
,
Raisch
D
,
P
,
Goldsmith
RJ
,
Ling
W
,
Malkerneker
U
,
McNicholas
L
,
Renner
J
,
Stine
S
,
Tusel
D
;
Buprenorphine/Naloxone Collaborative Study Group
:
Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.
N Engl J Med
2003
;
349
:
949
58
33.
Kamien
JB
,
Branstetter
SA
,
Amass
L
:
Buprenorphine-naloxone versus methadone maintenance therapy: A randomised double-blind trial with opioid-dependent patients.
Heroin Addict & Rel Clinical Problems
2008
;
10
:
5
18
34.
Raisch
DW
,
Fye
CL
,
Boardman
KD
,
Sather
MR
:
Opioid dependence treatment, including buprenorphine/naloxone.
Ann Pharmacother
2002
;
36
:
312
21
35.
Rapeli
P
,
Fabritius
C
,
Alho
H
,
Salaspuro
M
,
Wahlbeck
K
,
Kalska
H
:
Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: A naturalistic comparison of cognitive performance relative to healthy controls.
BMC Clin Pharmacol
2007
;
7
:
5
36.
Neumann
AM
,
Blondell
RD
,
Jaanimägi
U
,
Giambrone
AK
,
Homish
GG
,
Lozano
JR
,
Kowalik
U
,
M
:
A preliminary study comparing methadone and buprenorphine in patients with chronic pain and coexistent opioid addiction.
2013
;
32
:
68
78
37.
Kreek
MJ
,
LaForge
KS
,
Butelman
E
:
Nat Rev Drug Discov
2002
;
1
:
710
26
38.
Rosenblum
A
,
Marsch
LA
,
Joseph
H
,
Portenoy
RK
:
Opioids and the treatment of chronic pain: Controversies, current status, and future directions.
Exp Clin Psychopharmacol
2008
;
16
:
405
16
39.
Rosen
K
,
Gutierrez
A
,
Haller
D
,
Potter
JS
:
Sublingual buprenorphine for chronic pain: A survey of clinician prescribing practices.
Clin J Pain
2013
40.
Mao
J
:
Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy.
Pain
2002
;
100
:
213
7
41.
Angst
MS
,
Clark
JD
:
Opioid-induced hyperalgesia: A qualitative systematic review.
Anesthesiology
2006
;
104
:
570
87
42.
Walsh
SL
,
Preston
KL
,
Stitzer
ML
,
Cone
EJ
,
Bigelow
GE
:
Clinical pharmacology of buprenorphine: Ceiling effects at high doses.
Clin Pharmacol Ther
1994
;
55
:
569
80
43.
Daitch
J
,
Frey
ME
,
Silver
D
,
Mitnick
C
,
Daitch
D
,
Pergolizzi
J
Jr
:
Conversion of chronic pain patients from full-opioid agonists to sublingual buprenorphine.
Pain Physician
2012
;
15
(
3 suppl
):
ES59
66
44.
PA
,
Cardon
KE
,
Hoffman
RM
,
Geppert
CM
:
Prescription opioid abuse, chronic pain, and primary care: A Co-occurring Disorders Clinic in the chronic disease model.
J Subst Abuse Treat
2012
;
43
:
446
50
45.
Roux
P
,
Sullivan
MA
,
Cohen
J
,
Fugon
L
,
Jones
JD
,
Vosburg
SK
,
Cooper
ZD
,
Manubay
JM
,
Mogali
S
,
Comer
SD
:
Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: Reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone.
Pain
2013
;
154
:
1442
8
46.
Kamei
J
,
Saitoh
A
,
Suzuki
T
,
Misawa
M
,
Nagase
H
,
Kasuya
Y
:
Buprenorphine exerts its antinociceptive activity via mu 1-opioid receptors.
Life Sci
1995
;
56
:
PL285
90
47.
Koppert
W
,
Ihmsen
H
,
Körber
N
,
Wehrfritz
A
,
Sittl
R
,
Schmelz
M
,
Schüttler
J
:
Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model.
Pain
2005
;
118
:
15
22
48.
Lutfy
K
,
Eitan
S
,
Bryant
CD
,
Yang
YC
,
N
,
Walwyn
W
,
Kieffer
BL
,
Takeshima
H
,
Carroll
FI
,
Maidment
NT
,
Evans
CJ
:
Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.
J Neurosci
2003
;
23
:
10331
7
49.
Gardell
LR
,
Wang
R
,
Burgess
SE
,
Ossipov
MH
,
Vanderah
TW
,
Malan
TP
Jr
,
Lai
J
,
Porreca
F
:
Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers.
J Neurosci
2002
;
22
:
6747
55
50.
Lee
M
,
Silverman
SM
,
Hansen
H
,
Patel
VB
,
Manchikanti
L
:
A comprehensive review of opioid-induced hyperalgesia.
Pain Physician
2011
;
14
:
145
61
51.
Steiner
DJ
,
Sitar
S
,
Wen
W
,
Sawyerr
G
,
Munera
C
,
Ripa
SR
,
Landau
C
:
Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: An enriched, randomized, double-blind, placebo-controlled study.
J Pain Symptom Manage
2011
;
42
:
903
17
52.
Mitra
F
,
Chowdhury
S
,
Shelley
M
,
Williams
G
:
A feasibility study of transdermal buprenorphine versus transdermal fentanyl in the long-term management of persistent non-cancer pain.
Pain Med
2013
;
14
:
75
83
53.
Yarlas
A
,
Miller
K
,
Wen
W
,
Dain
B
,
Lynch
SY
,
Pergolizzi
JV
,
Raffa
RB
,
Ripa
SR
:
A randomized, placebo-controlled study of the impact of the 7-day buprenorphine transdermal system on health-related quality of life in opioid-naïve patients with moderate-to-severe chronic low back pain.
J Pain
2013
;
14
:
14
23
54.
Breivika
H
,
Ljosaaa
TM
,
Stengaard-Pedersenb
K
,
J
,
Arod
H
,
Villumsene
J
,
Tvinnemose
D
:
A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids.
Scandinavian J Pain
2010
;
1
:
122
41
55.
S
,
Porzio
G
,
Ferrera
P
,
Aielli
F
,
Verna
L
,
Tirelli
W
,
Villari
P
,
Casuccio
A
:
Low doses of transdermal buprenorphine in opioid-naive patients with cancer pain: A 4-week, nonrandomized, open-label, uncontrolled observational study.
Clin Ther
2009
;
31
:
2134
8
56.
Sittl
R
,
Griessinger
N
,
Likar
R
:
Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial.
Clin Ther
2003
;
25
:
150
68
57.
Böhme
K
:
Buprenorphine in a transdermal therapeutic system—A new option.
Clin Rheumatol
2002
;
21
(
suppl 1
):
S13
6
58.
Griessinger
N
,
Sittl
R
,
Likar
R
:
Transdermal buprenorphine in clinical practice—A post-marketing surveillance study in 13,179 patients.
Curr Med Res Opin
2005
;
21
:
1147
56
59.
Malinoff
HL
,
Barkin
RL
,
Wilson
G
:
Sublingual buprenorphine is effective in the treatment of chronic pain syndrome.
Am J Ther
2005
;
12
:
379
84
60.
Berland
DW
,
Malinoff
HL
,
Weiner
MA
,
Przybylski
R
:
When opioids fail in chronic pain management: The role for buprenorphine and hospitalization.
Am J Ther
2013
;
20
:
316
21
61.
Ferrari
A
,
Coccia
CP
,
Bertolini
A
,
Sternieri
E
:
Pharmacol Res
2004
;
50
:
551
9
62.
Chhabra
S
,
Bull
J
:
Am J Hosp Palliat Care
2008
;
25
:
146
50
63.
Sotgiu
ML
,
Valente
M
,
Storchi
R
,
Caramenti
G
,
Biella
GE
:
Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain.
Pharmacol Res
2009
;
60
:
284
90
64.
Davis
MP
,
Walsh
D
:
Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration.
Support Care Cancer
2001
;
9
:
73
83
65.
Ripamonti
C
,
Zecca
E
,
Bruera
E
:
An update on the clinical use of methadone for cancer pain.
Pain
1997
;
70
:
109
15
66.
Inturrisi
CE
,
Colburn
WA
,
Kaiko
RF
,
Houde
RW
,
Foley
KM
:
Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain.
Clin Pharmacol Ther
1987
;
41
:
392
401
67.
Caplehorn
JR
,
Drummer
OH
:
Fatal methadone toxicity: Signs and circumstances, and the role of benzodiazepines.
Aust N Z J Public Health
2002
;
26
:
358
62; discussion 362–3
68.
Boyer
EW
,
McCance-Katz
EF
,
Marcus
S
:
Methadone and buprenorphine toxicity in children.
2010
;
19
:
89
95
69.
Davis
MP
:
Twelve reasons for considering buprenorphine as a frontline analgesic in the management of pain.
J Support Oncol
2012
;
10
:
209
19
70.
Darke
S
,
Duflou
J
,
Torok
M
:
The comparative toxicology and major organ pathology of fatal methadone and heroin toxicity cases.
Drug Alcohol Depend
2010
;
106
:
1
6
71.
Bryson
EO
,
Lipson
S
,
Gevirtz
C
:
Anesthesia for patients on buprenorphine.
Anesthesiol Clin
2010
;
28
:
611
7
72.
Roberts
DM
,
Meyer-Witting
M
:
High-dose buprenorphine: Perioperative precautions and management strategies.
Anaesth Intensive Care
2005
;
33
:
17
25