Clinical Use of Buprenorphine for Anesthesia and Pain Management in Japan

Buprenorphine (BUP) is a classic analgesic drug, and recent studies have reported a new, unique pharmacological profile of it. BUP can be used in patients with renal dysfunction and failure, and these patients can receive the same dose of BUP administered to those with normal renal function. BUP may have a local anestheticlike effect to blockade voltage gated Na+ channels; it can be used as a local anesthetic peripheral nerve block adjuvant to prolong analgesia. BUP is useful for postoperative pain relief in patients with severe liver dysfunction in Japan. However, the prolonged metabolism of BUP and occurrence of delayed emergence from anesthesia may occur in these patients. Moreover, in Japan, the transdermal buprenorphine patch (TBP) is used for the reducing intractable chronic non-cancer pain such as low back pain or pain caused by osteoarthritis not opioid addiction.


Introduction
Buprenorphine (BUP), a classic chemically synthesized opioid reported in 1967 by Bentley et al. [1], has been reconsidered as an analgesic for anesthesia or the management of postoperative pain and cancer pain. Moreover, recent studies have also reported a new, unique pharmacological profile of BUP [2].
On the other hand, transdermal buprenorphine patch (TBP) has been widely used in pain medicine since 2011 to reduce chronic noncancer pain in Japan. However, the use is limited for reducing low back pain or joint pain in Japan. Simultaneously, BUP is reconsidered as a useful postoperative analgesic after general anesthesia with remifentanil.
Therefore, I will present the recent clinical significance of BUP in Japan for anesthesia, postoperative pain management, and chronic pain management in this short review.

Recent Knowledge of Pharmacokinetics of BUP
It is well known, BUP is synthesized from thebaine (paramorphine) [1], an opioid alkaloid, and it has a chemical structure similar to morphine (MOR) and codeine. BUP has the affinity of Ki of 0.16 nM against the human recombinant μ receptor and Ki of 0.06 nM against the κ receptor [3]. In addition, BUP has an efficacy of EC50>20,000 nM against the κ receptor compared to an EC50 of 0.76 nM for the μ receptor. Therefore, BUP is currently considered a partial agonist of μ-1 and μ-2 receptors and a partial antagonist of κ-1 receptor. However, recent investigations have reported that BUP is a potent, partial agonist of the μ-1, μ-2, κ, and δ subunits, especially the κ-3 subunit [2]. BUP has 40 times more than MOR in the analgesic effect; nevertheless, the binding effect to the mu receptor is lower for BUP than for MOR [4]. Moreover, as a partial agonist of the nociceptin/ orphanin FQ (opioid receptor like-1) receptor, BUP induces an analgesic effect on the spinal cord and inhibits opioid tolerance, opioid-induced hyperalgesia, and the rewarding effect caused by opioids [5]. Norbuprenorphine (NBUP), a metabolite of Ndealkylation of BUP, is a full agonist of the δ receptor and partial agonist of the mu and κ receptors [6]. Compared to BUP, NBUP has a high affinity for the μ, κ, and δ receptors. However, because NBUP cannot pass through the blood-brain barrier (BBB), the pharmacological effect of NBUP is weak.
BUP is excreted in the feces through the bile, which undergoes glucuronidation in the liver, so the renal excretion rate is about 1%. Therefore, BUP can be used in patients with renal dysfunction and even in those on dialysis due to renal failure; these patients can receive the same dose of BUP administered to those with normal renal function [7]. BUP may also have a local anesthetic-like effect to blockade voltage-gated Na + channels [8]. Thus, BUP can be used as a local anesthetic peripheral nerve block adjuvant to prolong analgesia [9]. As the response from the μ receptor is slower to BUP than to other opioids, withdrawal symptoms of BUP are usually not seen, as there is a ceiling effect. Therefore, there is little risk of dependency, and tolerance is inhibited. The rewarding effect caused by opioids is also mild compared to that of MOR, as the rewarding effects are only observed at higher doses [7]. Therefore, BUP is considered an opioid with a low risk of abuse or addiction [10].

Clinical Use of BUP for Anesthesia in Japan
Usually, the injection of BUP is used to assist in the management of anesthesia [11]. Changes in the blood concentration of patients who received BUP intravenously and intramuscularly are equal, and the duration of BUP is reported as 6-9 hours. For the relief of postoperative pain, 4-5 μg/kg of a single dose of BUP is administered intravenously [12].
According to the several Japanese trial of BUP by Japanese researchers in 1982, the effective rates of BUP at 4 µg/kg, 6 µg/kg and 8 µg/kg to support anesthesia are reportedly 50.0%, 83.3%, and 83.9%, respectively (article in Japanese only). Therefore, in Japan, it is recommend administering 6 μg/kg of BUP to support anesthesia and 4-5 μg/kg of a single dose of BUP for postoperative pain relief.
Moreover, a continuous subcutaneous infusion of 0.6-0.7 mg/d and continuous intravenous infusion of 0.002 mg/kg/h of BUP are recommended for postoperative main management according reports by Gourlay or Bramley et al. [13,14].
I will mention the more common usage of BUP in Japan as below.

BUP for postoperative pain relief in hepatic dysfunction patients
As the previous report, BUP provides effective postoperative pain relief, and it did not compromise the recovery of patients who underwent major abdominal surgery with total intravenous anesthesia [15]. Especially, we considered that, in cases of partial liver resection cause of liver cancer, the use of BUP for postoperative pain management after remifentanil-based anesthesia with a volatile anesthetic has been indicated. Most patients with liver cancer caused by liver cirrhosis may have coagulation dysfunction. Thus, epidural analgesia cannot be chosen for postoperative pain relief [16,17].
For subsequent analgesia from the intraoperative period in the surgical theater to the postoperative period in the ward, we recommended the administration of 5 μg/kg of BUP before the end of surgical procedure and remifentanil-based anesthesia like the method of Kimoto et al [18]. There might be no significant difference regarding recovery from anesthesia to extubation between patients who underwent liver resection and did or did not receive small dose of BUP [19].
Usually, it is best to interrupt BUP therapy 6-8 hours before anesthesia [20], because the high affinity of BUP prevents the binding of other opioids such as fentanyl or remifentanil at commonly used clinical doses to receptor sites, which reduces their minimum alveolar concentration (MAC).
However, there are several studies about the usefulness of BUP for postoperative pain relief without delayed emergence from anesthesia [15,21,22]. Particularly, Albrecht et al. [15] emphasized the efficacy of piritramide over fentanyl and BUP. Since piritramide cannot be used in Japan, we use BUP for postoperative pain management, as it has the same effect as fentanyl. Since BUP undergoes hepatic metabolism, it is likely to have a prolonged effect in patients with liver disease [23]. Thus, severe liver dysfunction may prolong the metabolism of BUP and cause delayed emergence from anesthesia. In patients with hepatic dysfunction, the use of most analgesics is limited due to significantly impaired renal clearance, but this has been poorly studied in the clinical setting. On the other hand, BUP has the risk of postoperative delirium in elderly patients [24].

Transdermal BUP for chronic non-cancer pain treatment
In 2011, the TBP was first used in clinical practice for treating chronic musculoskeletal pain [25,26]. In Japan, we can only use TBP, not sublingual BUP or the BUP/naloxone compound for non-cancer pain relief. BUP with naloxone is a well-known therapeutic agent for opioid addiction. But, there is no clinical use of BUP to treat the opioid addiction. Therefore, BUP is evaluated as the analgesic only in Japan and that is different from that in other countries such as the United States or Europe [27].
TBP is useful for reducing chronic non-cancer low back pain and pain due to osteoarthritis; these types of pain are difficult to treat with non-opioid analgesics [28,29]. Three doses of TBP may be used (5 mg, 10 mg, and 20 mg); the maximum serum concentration are as follows: 84 ± 19 pg/mL, 140 ± 47 pg/mL, and 270 ± 67 pg/mL, respectively. The tendency to treat non-cancer chronic pain with TBP was retrospectively reviewed [27]. Safety index (odds ratio of the antinociceptive effect / odds ratio of respiratory depression) of BUP is 13.54, whereas the safety index of fentanyl is 1.20. This result indicates that the safety margin of BUP is wide compared to that of fentanyl [30]. Recently, Dowell et al. indicated that for patients with an opioid use disorder, clinicians should offer or plan to use evidence-based treatment such as medication-assisted treatment with BUP or methadone [31].
Regarding side effects, constipation, nausea, and vomiting are seen at a high rate. Therefore, it is necessary to combine BUP with antiemetics and laxatives. Often the incidence of constipation caused by BUP is less than that due to MOR. In patients taking oral Pglycoprotein inhibitors, there is a possibility that NBUP may easily pass through the BBB and thus enhance the analgesic effect [32]. Therefore, patients who are taking drugs such as verapamil, amiodarone, quinidine, an immunosuppressive agent, and HIV therapeutic agents that have the ability to inhibit P-glycoprotein may enhance the analgesic effect of BUP.

Conclusion
BUP is a well-known synthesized opioid analgesic with unique properties such as being a partial κ agonist and Na+ channel blocker [2,8]. However, further study is required to assess the safety of perioperative pain management and chronic pain management with BUP in the future.

Funding
This report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of Interest
The author declares no conflicts of interest.