Is Buprenorphine a ‘Partial Agonist’? Preclinical and Clinical Evidence
It has become commonplace for buprenorphine to be referred to as a ‘partial agonist,’ with no reason given. It seems that this characterization is based mainly on in vitro laboratory assay results, rather than on in vivo testing or clinical data. Because buprenorphine is well suited for transdermal patch delivery and is increasingly prescribed in this formulation for pain relief, misperceptions based on the characterization of the drug as a partial agonist can lead to sub-optimal use.
This article reviews criteria and evidence to assist in answering the question of whether buprenorphine should be termed a partial agonist.
What is Buprenorphine?
Buprenorphine is commercially available in a variety of formulations (Table 1), and although it is increasingly prescribed, it has been pointed out that erroneous beliefs about its mechanism of action and adverse effect profile persist.1 Its use as an important alternative to methadone for maintenance treatment of opioid-dependent patients has diverted some attention from its role as an analgesic. However, buprenorphine has a unique pharmacological profile,2 and while much remains to be learned, it is clear that it is an important treatment option for the management of moderate to severe cancer and non-cancer pain syndromes.
A growing body of literature elucidates the intriguing and complex pharmacology of buprenorphine. It has been studied in laboratory assays, animal models, and human clinical trials. These studies measure three related, but distinct, basic pharmacological properties: affinity, intrinsic activity, and analgesic efficacy (Figure 1). Affinity represents the fundamental chemical interaction between a ligand and a receptor.3 Intrinsic activity represents the fundamental biological stimulus imparted by an agonist at a receptor.4 Both of these properties are inherent to the specific physiochemical properties and complementary conformational features of the ligand and the receptor. Efficacy, as a single word, has been used to mean the same thing as intrinsic activity or some variation thereof incorporating several aspects of a drug-receptor interaction.5 A more clinically-relevant term is x–efficacy, meaning level of x clinical effect (eg, x = analgesic efficacy). The use of the word efficacy in both ways has led to some confusion, in particular when used to describe buprenorphine.
Buprenorphine possesses a very high affinity for the μ-opioid receptor (MOR).6 That is, it has high potency in these assays, even higher than that of morphine. However, it displays low intrinsic activity in in vitro (test tube) assays, as determined by [35S]GTPyS binding.7,8 This is the major data source that has led to the characterization of buprenorphine as a partial agonist, a compound that produces less than the 100% effect produced by a full agonist. The problem is that 100% depends on the conditions. For example, in the same in vitro assays in which buprenorphine is a partial agonist, so is morphine. Yet, most people would not consider morphine to be a partial agonist in clinical practice. McCormack et al state: ". . . any opioid agonist may become a partial agonist given a stimulus of sufficient intensity which causes the agonist to surpass its receptor reserve."9
This further highlights the importance of using precise terminology. In vitro assays provide very good measures of a drug’s affinity and intrinsic activity, but they are not good predictors of in vivo analgesic efficacy. For example, loperamide has high affinity and intrinsic activity at opioid receptors, but it does not display any central nervous system opioid activity because it does not cross the blood-brain barrier. Its analgesic efficacy is zero. Thus, analgesic efficacy must be measured in the relevant conditions. Under these conditions, the question is: "how much intrinsic activity is needed?" With reference to Figure 1, one drug has greater intrinsic activity than the other, but both levels of intrinsic activity are sufficient to reach the necessary level of analgesic effect. Thus, both drugs produce 100% of the required level of pain relief (the relative intrinsic activity becomes irrelevant above the threshold) and both are properly termed a "full agonist" under these specified conditions. The results might be different under different conditions; that is why the designation "full" or "partial" agonist is a conditional term (ie, situation dependent). The question then becomes: "is buprenorphine a partial agonist in analgesic tests?"
In a large variety of preclinical pain models, buprenorphine displays antinociceptive efficacy against acute, inflammatory, visceral, and neuropathic pain (Figure 2).10 In the majority of these tests, buprenorphine displays at least 98% antinociceptive efficacy and in only a few does it display less than 90% antinociceptive efficacy.
Buprenorphine is not associated with an analgesic ceiling effect in humans at doses from 0.2 to about 7 mg.11 Positron emission tomography (PET) scans of human brains have shown that full analgesia is achieved with buprenorphine at doses that occupy less than 100% of MOR (assessed as displacement of [11C]carfentanil) (Figure 3).12 This is the definition of a full agonist.
A relatively new formulation of buprenorphine allows for transdermal drug delivery through an adhesive skin patch. Due to its lipophilic nature and small molecule size, buprenorphine appears particularly well suited to transdermal delivery. As part of the regulatory approval process, transdermal buprenorphine was tested in clinical trials, which provide an opportunity to assess analgesic efficacy in a variety of clinical pain syndromes. Table 2, summarizes the most recent studies involving the clinical efficacy of buprenorphine.13-19
The analgesic efficacy of buprenorphine has been shown to be equivalent to that of morphine in acute pain management (Figure 4).20
Based on package insert information, patients who are prescribed <30 mg of morphine (or <90 mg codeine, <300 mg tramadol, or <15 mg oxycodone) may be converted to transdermal buprenorphine 5 mcg/h, whereas those prescribed 30 to 80 mg of morphine (or 90-250 mg of codeine, 300-400 mg of tramadol, or 15-40 mg of oxycodone) may be prescribed the 10 mcg/h patch. Patients taking >80 mg of morphine or equivalent may not be suitable candidates for transdermal buprenorphine.