General Opioid Pharmacology

Opioid Receptors

Opioid receptors are molecules on the surfaces of cells to which . opioid compounds attach and through which they exert their effects. Different types of opioid receptors are present in the brain. The receptor most relevant to opioid abuse and treatment is the mu receptor. It is through activation of the mu receptor that opioids exert their analgesic, euphorigenic, and addictive effects. The roles of other types of opioid receptors in the brain (that is, non-mu opioid receptors) in the addictive process are not well defined.

The Functions of Opioids at Receptors

Opioids can interact with receptors in different ways. For purposes of this discussion, three types of drug/receptor interactions are described: agonists (or full agonists), antagonists, and partial agonists.

 Full Agonists  

Drugs that activate receptors in the brain are termed agonists. Agonists bind to receptors and turn them on - they produce an effect in the organism. Full mu opioid agonists activate mu receptors. Increasing doses of full agonists produce increasing effects until a maximum effect is reached or the receptor is fully activated. Opioids with the greatest abuse potential are full agonists (e.g., morphine, heroin, methadone, oxycodone, hydromorphone).

Antagonists

Antagonists   also   bind   to   opioid   receptors,   but    instead  of activating receptors, they effectively block them. Antagonists do not activate receptors, and they prevent receptors from being activated by agonist compounds. An antagonist is like a key that fits in a lock but does not open it and prevents another key from being inserted to open the lock. Examples of opioid antagonists are naltrexone and naloxone.

Partial Agonists

Partial agonists possess some of the properties of both antagonists and  full agonists. Partial agonists bind to receptors and activate them, but not to the same degree as do full agonists. At lower doses and in individuals who are not dependent on opioids, full agonists and partial agonists produce effects that are indistinguishable. As doses are increased, both full and partial agonists produce increasing effects. At a certain point, however, the increasing effects of partial agonists reach maximum levels and do not increase further, even if doses continue to rise - the ceiling effect.

The figure represents any effect mediated by mu opioid receptors (e.g., analgesia, euphoria, respiratory depression). As higher doses are reached, partial agonists can act like antagonists occupying receptors but not activating them (or only partially activating them), while at the same time displacing or blocking full agonists from receptors. Buprenorphine is an example of a mu opioid partial agonist, and its properties as such are discussed in detail below.  

Conceptual representaion only, not to be used for dosing purposes. 

Consequences of Repeated Administration and Withdrawal of Opioid Drugs

The repeated administration of a mu opioid agonist results in tolerance and dose-dependent physical dependence. Tolerance is characterized by a decreased subjective and objective response to the same amount of opioids used over time or by the need to keep increasing the amount used to achieve the desired effect. In the case of abuse or addiction, the desired effect typically is euphoria. Physical dependence is manifested as a characteristic set of withdrawal signs and symptoms in response to reduction, cessation, or loss of the active compound at receptors (withdrawal syndrome).

Typical   signs   and   symptoms  of     the   opioid    withdrawal syndrome include lacrimation, diarrhea, rhinorrhea, piloerection, yawning, cramps and aches, pupillary dilation, and sweating. Not all of these signs and symptoms are necessarily present in any single individual experiencing the opioid withdrawal syndrome. Withdrawal, characterized by marked distress, may include drug craving and drug seeking and is frequently associated with relapse to drug use in a patient with opioid addiction.

 In an individual who otherwise is in good general health (e.g., with no history of significant cardiovascular disease), opioid withdrawal is not life threatening. Patients with cardiovascular disease or other severe conditions will need co-management involving the appropriate specialist, as well as consultation with an addiction specialist.

Two types of withdrawal are associated with mu opioid agonists: spontaneous withdrawal and precipitated withdrawal.

Spontaneous Withdrawal

Spontaneous  withdrawal  can  occur  when an individual when an individual who is physically dependent on mu agonist opioids (e.g., has been using opioids on daily basis) suddenly discontinues that opioid use. It can also occur if an individual who is physically dependent markedly decreases his or daily opioid use

If an individual who is  physically  dependent on heroin, spontaneous withdrawal usually begins 6-12 hours after the last dose and peaks in intensity 36-72 hours after the last use.  The spontaneous withdrawal syndrome from heroin lasts approximately 5 days, although a milder, protracted withdrawal may last longer. Other short-acting opioids, such as oxycodone and hydrocodone, have kinetic profiles that are similar to heroin, and the time course of spontaneous withdrawal for these agents should be similar to that documented for heroin. Opioids with longer half-lives have a longer period before the onset of spontaneous withdrawal (e.g., 24-72 hours for methadone) and a longer period before peak withdrawal is experienced.

Precipitated Withdrawal

Precipitated  withdrawal  also  occurs  in i ndividuals  who  are physically dependent on mu agonist opioids. Precipitated withdrawal usually occurs when an individual physically dependent on opioids is administered an opioid antagonist.In an individual who is not physically dependent upon opioids, the acute administration of an antagonist typically produces no effects. In an individual who is physically dependent on opioids, however, an antagonist produces a syndrome of withdrawal that is qualitatively similar to that seen with spontaneous withdrawal (although the onset is faster and the syndrome is shorter, depending on the half -life of the antagonist). One way to conceptualize precipitated withdrawal is that the antagonist displaces agonists from receptors, but because the antagonist does not activate the receptor, there is a net decrease in agonist effect, resulting in withdrawal.

It is also possible for partial agonists to precipitate withdrawal. If an individual who is physically dependent on opioids receives an acute dose of a partial agonist, the partial agonist can displace the full agonist from the receptors yet not activate the receptors as much as the full agonist had. The net effect would be a decrease in agonist effect and a precipitated withdrawal syndrome. Precipitated withdrawal with a partial agonist is more likely to occur in an individual who has a high level of physical dependence (e.g., high use of opioids each day), who takes the partial agonist soon after a dose of full agonist, and/or who takes a high dose of the partial agonist. These points, discussed in more detail below, are directly relevant to the initiation of buprenorphine treatment.

Affinity, Intrinsic Activity, and Dissociation

The strength with which a drug binds to its  receptor is  termed its affinity. The degree to which a drug activates its receptors is termed its intrinsic activity. Affinity for a receptor and activation of the receptor are two different qualities of a drug. A drug can have high affinity for a receptor but not activate the receptor (e.g., an antagonist). Mu opioid agonists, partial agonists, and antagonists can vary in their affinity.

In addition to variations in affinity and intrinsic activity, drugs also vary in their rate of dissociation from receptors. Dissociation is a measure of the disengagement or uncoupling of the drug from the receptor. Dissociation is not the same as affinity- a drug can have high affinity for a receptor (it is difficult to displace it from the receptor with another drug once the first drug is present), but it still dissociates or uncouples from the receptor with some regularity. Buprenorphine's slow dissociation contributes to its long duration of action.

Characteristics of Abused Drugs

The rate of onset of the pharmacological effects of a drug, and thereby its abuse potential, is determined by a number of factors. Important among these are the drug's route of administration, its half-life, and its lipophilicity (which determines how fast the drug reaches the brain). A faster route of drug administration (e.g., injection, smoking), a shorter half -life, and a faster onset of action all are associated with a higher abuse potential of a drug. With all classes of drugs of abuse, it has been shown that the likelihood of abuse is related to the ease of administration, the cost of the drug, and how fast the user experiences the desired results after the drug's administration. In this respect, heroin is highly abusable, as it currently is inexpensive; can be snorted, smoked, or injected; and produces a rapid euphorigenic response.

Pharmacology Of Buprenorphine

Buprenorphine is a thebaine derivative that is legally classified as a narcotic. It is available in numerous countries for use as an analgesic.  When used as an analgesic, buprenorphine is usually given by injection,via a sublingual tablet,or as a transdermal patch and doses are relatively low (compared with doses used in the treatment of opioid addiction).  The typical analgesic dose of buprenorphine is 0.3-0.6mg (intramuscular or intravenous),and its analgesic effects last about six hours. 

Buprenorphine is a partial agonist that exerts significant actions at the mu opioid receptor. As reviewed in the previous section, however, its maximal opioid effects are less than that of full agonists, and reach a ceiling where higher doses do not result in increasing effect. Because it is a partial agonist, higher doses of buprenorphine can be given with fewer adverse effects (e.g., respiratory depression) than are seen with higher doses of full agonist opioids. Past a certain point, dose increases of buprenorphine do not further increase the pharmacological effects of the drug but do increase its duration of withdrawal suppression and opioid blockade.

At low doses, buprenorphine is many  times  more  potent than morphine. Individuals who are not dependent on opioids but who are familiar with the effects of opioids experience a subjectively positive opioid effect when they receive an acute dose of buprenorphine. These subjective effects aid in maintaining compliance with buprenorphine dosing in patients who are addicted to opioids.

Affinity, Intrinsic Activity, and Dissociation

Buprenorphine has high affinity for, but low intrinsic activity at, mu receptors. Buprenorphine displaces morphine, methadone, and other full opioid agonists from receptors. It also can block the effects of other opioids (Bickel et al. 1988b ; Rosen et al.  1994; Strain et al. 2002). Because of buprenorphine's higher affinity for the mu receptor, full agonists cannot displace it and therefore will not exert an opioid effect on receptors already occupied by buprenorphine. This effect is dose related, as shown by Comer et al. (2001) in a study demonstrating that the 16-mg dose of the sublingual buprenorphine-alone tablet was more effective than the 8-mg dose in blocking the reinforcing effects of heroin. Similarly, it is difficult for opioid antagonists (e.g., naloxone) to displace buprenorphine and precipitate withdrawal.

Buprenorphine has a slow dissociation rate from the mu opioid receptor, which gives rise to its prolonged suppression of opioid withdrawal andblockade of exogenous opioids. This enables buprenorphine dosing to occur on a less frequent basis than full opioid agonists (Amass et al. 1994a, b, 1998, 2000 2001). Buprenorphine can be given as infrequently as three times per week (Amass et al. 2001; Perez de los Cobos et al. 2000; Schottenfeld et al. 2000). Buprenorphine's effectiveness as a medication for the treatment of opioid addiction on a daily or less-than-daily basis contrasts with its relatively short duration of action as an analgesic.

Bioavailability

Buprenorphine has  poor   gastrointestinal  (GI)   bioavailability (Brewster et al. 1981; Walter and Inturrisi 1995), and fair sublingual bioavailability. FDA-approved formulations of the drug for treatment of opioid addiction are in the form of sublingual tablets that are held under the tongue and absorbed through the sublingual mucosa. Studies of sublingually administered buprenorphine have employed either an alcohol-based solution or a tablet formulation of the drug. Confusion may result when reviewing the literature on the effectiveness of buprenorphine at various doses because most early trials and clinical studies of buprenorphine were performed with a sublingually administered liquid preparation, whereas the oral formulations marketed in the United States are sublingual tablets. Studies have shown that the bioavailability of buprenorphine in sublingual tablet form is significantly less than via sublingual liquid solution about 50-70 percent that of the liquid form (Nath et al. 1999; Schuh and Johanson 1999), so the dosages of buprenorphine sublingual tablets must be significantly higher than those used in the liquid form to achieve the same therapeutic effect.

Abuse Potential

Epidemiological studies and human laboratory studies indicate that buprenorphine is abusable. This is consistent with its action at the mu opioid receptor. The abuse potential, however, is lower in comparison with the abuse potential of full opioid agonists. This is consistent with buprenorphine's partial agonist effects and the resultant ceiling in maximal effects produced. Still, abuse of the analgesic form of buprenorphine through diversion to the injectable route has been reported internationally:

England (Strang 1985)

Ireland (O'Connor et al. 1988)

Scotland (Gray et al. 1989; Morrison 1989; Sakol et al. 1989)

India (Chowdhury and Chowdhury 1990; Singh et al. 1992)

New Zealand (Robinson et al. 1993)

Abuse of buprenorphine has been reported to occur via the sublingual and intranasal routes but primarily via diversion of sublingual tablets to the injection route.In a study from France (Obadia et al. 2001), sublingual, buprenorphine-only tablets (Subutex), marketed for the treatment of opioid addiction, were diverted to the injection route.

Laboratory studies with inpatient subjects have examined the effects of buprenorphine relevant to abuse potential in two populations:(1) subjects who have a history of opioid abuse but are not physically dependent on opioids, and (2) subjects who are physically dependent on opioids.

Abuse Potential in Nonphysically Dependent Opioid Users

In  nonphysically  dependent  opioid  users,  acute  parenteral doses of buprenorphine produce typical mu agonist opioid effects (e.g., pupillary constriction, mild euphoria), suggesting that this population could abuse buprenorphine (Jasinski et al. 1978, 1989; Pickworth et al. 1993).

Similar effects can occur in this population when buprenorphine is administered via other routes, including the sublingual route (Jasinski et al. 1989; Johnson et al. 1989; Walsh et al. 1994). Strain et al. (2000) recently reconfirmed the opioid-like effects of sublingually administered buprenorphine in this population. These researchers further found that, in nondependent subjects, the addition of naloxone (in the buprenorphine/naloxone combination tablet) did not attentuate buprenorphine's opioid effects via the sublingual route. The onset of effects via the sublingual route is slower than that seen with parenteral administration, suggesting that the abuse potential by this route is lower than via the parenteral route.

Abuse Potential in Physically Dependent Opioid Users  

The abuse potential of buprenorphine in individuals who are physically dependent on opioids varies as a function of three factors:(1) level of physical dependence, (2) time interval between administration of the full agonist and of buprenorphine, and (3) the dose of buprenorphine administered.

(1)  Level of Physical Dependence.

 In individuals with a high level of physical dependence (e.g., those using substantial amounts of opioids on a daily basis), buprenorphine may precipitate withdrawal when taken during the time of opioid intoxication or receptor occupancy.. The relationship between level of physical dependence and buprenorphine-related precipitated withdrawal has been investigated primarily in subjects maintained on methadone.

For example, patients maintained on 60 mg of methadone daily can experience precipitated withdrawal from acute doses of sublingual buprenorphine (Walsh et al. 1995).

Conversely, in individuals with a low level of physical dependence (e.g., patients maintained on <30 mg per day of methadone), buprenorphine could produce opioid agonist effects, thus suggesting a potential for abuse.

(2)  Time Interval

The abuse potential of buprenorphine in opioid dependent individuals also varies as a function of the time interval between the dose of agonist and the dose of buprenorphine. At relatively short time intervals (e.g.,2 hours after a dose of methadone), buprenorphine can precipitate withdrawal even when the level of physical dependence is relatively low (Strain et al. 1995). At longer time intervals, it becomes more likely that buprenorphine will exhibit either no effects (i.e., similar to placebo [Strain et al. 1992]) or effects similar to opioid agonists.

(3)  Acute Dose of Buprenorphine.

Finally, the dose of buprenorphine administered also can influence its abuse potential. Low doses of injected buprenorphine(e.g., ≤2 mg) produce minimal effects in opioid -dependent patients and are primarily identified as similar to placebo (Strain et al. 1992) although there has been at least one report of more precipitated abstinence (Banys et al. 1994).

Higher doses can be identified as opioid agonist-like, especially as the time interval since the dose of agonist increases (e.g., 24 or more hours) and if the individual has a lower level of physical dependence (e.g., 30 mg per day of methadone or the equivalent).

Although buprenorphine can precipitate withdrawal under certain circumstances, it is worth noting that it does not usually produce severe precipitated withdrawal symptoms.

Potential for Physical Dependence

Repeated    administration   of   buprenorphine    produces   or maintains  opioid physical dependence; however, because buprenorphine is a partial agonist, the level of physical dependence appears to be less than that produced by full agonists (Eissenberg et al. 1996). Furthermore, the withdrawal syndrome associated with buprenorphine discontinuation may be significantly milder in intensity, and the onset of withdrawal signs and symptoms slower, than that seen with full mu agonists (Eissenberg et al. 1997; Jasinski et al. 1978; Mello et al. 1982; San et al. 1992). The reason for the slower onset of withdrawal symptoms is not completely understood but is likely related to buprenorphine's slow dissociation from the mu receptor. Gradual dose reduction of buprenorphine results in an even milder withdrawal syndrome.

Metabolism and Excretion

A high percentage of buprenorphine is bound to plasma protein and is metabolized in the liver by the cytochrome P450 3A4 enzyme system into norbuprenorphine and other products (Iribarne et al. 1997; Kobayashi et al. 1998). First-pass effects account for its relatively low GI bioavailability and its short plasma half -life. (See the buprenorphine package inserts for a more detailed explanation of its metabolism and excretion.)

Side Effects 

The primary side effects of buprenorphine are similar to other mu opioid agonists (e.g., nausea, vomiting, constipation), but the intensity of these side effects may be less than that produced by full agonist opioids.

Reference: (1) Clinical Guidelines ForThe Use of Buprenorphine In The Treatment  of  Opiate Addiction:  (Chapter 2)   Pharmacology (Tip 40)

Compiled and Edited By: Deborah Shrira
Updated:  17 March 2007