Partial mu agonists and agonist-antagonists: "Weak" opioids

Buprenorphine. Although it is a partial mu agonist, buprenorphine has a far greater affinity for mu receptors than morphine does and will, therefore, displace a pure mu agonist if both are present. There is a ceiling effect to this drug, providing a level of safety, but also a bell-shaped response curve (there may be some mu antagonism at higher doses). In addition, onset time and duration appear to be highly variable and may be dose-dependent.⁹ One of the chief benefits of buprenorphine is that in cats it results in minimal sedation and is nearly completely absorbed transmucosally, making it a convenient option for this species. This method of administration results in similar effects as with either intravenous or intramuscular injection.^8,10 About 40% to 50% is transmucosally absorbed in dogs, so higher doses than those used in cats are needed when administering it via this route.¹¹

Butorphanol. Butorphanol is a mu antagonist, kappa agonist (the latter promotes the production of inhibitory neurotransmitters such as GABA). It has a short duration in dogs,¹² with reported minimal analgesia and no anesthetic-sparing effect in a canine tail-clamp model,¹³ making it a poor choice for prolonged or pronounced analgesia in this species. However, it has a ceiling effect (thus, is safe) and when given parenterally, it has a synergistic effect with other medications such as alpha₂ agonists.

Naloxone. Naloxone has been used as an opioid reversal agent in cases of overdose or severe adverse effects. However, this reversal may be better accomplished with the use of a partial mu agonist such as buprenorphine or an antagonist-agonist such as butorphanol. This approach allows the adverse effects to diminish while maintaining analgesia. In people, ultra-low doses of naloxone have even been used to increase the analgesia provided by buprenorphine.¹⁴

ADVERSE EFFECTS

In the acute setting, pure mu agonists can cause respiratory depression; however, the degree of the problem appears to be less than it is in humans and it is usually confined in dogs and cats to high doses and when given intravenously. Any opioid can result in dysphoria, but the behavior (often vocalizing) can be difficult to distinguish from pain. Attempting to console or distract an animal may aid in distinguishing between dysphoria and pain. A rule of thumb is that dysphoric animals are difficult to calm out of their agitated state, and administration of additional opioids does not help this situation, while animals in pain can usually be temporarily distracted or calmed. In humans, pure mu agonists are also known to induce hyperalgesia in some patients, and this counterintuitive phenomenon may also occur occasionally in a dog or cat.

In veterinary medicine, unlike in human medicine, opioids are uncommonly used—and arguably underused—in patients with chronic pain. As opioids gain ground as effective analgesics for chronic pain, adverse effects commonly seen in human patients might also become apparent in dogs and cats. Constipation, abnormal pain sensitivity, and effects on gastrointestinal motility may need to be addressed in veterinary patients. With judicious use of opioids in dogs and cats, veterinarians probably do not have to be concerned about dependence issues in these patients; however, it is a sad fact that clinicians have to be alert to the possibility of drug diversion for human consumption.

Remember, a multimodal approach to pain therapy is the most effective way to avoid adverse events, reduce drug dose requirements, and maximize a patient's quality of life.

WHAT'S ON THE HORIZON?

Tapentadol is the first new class of analgesic drug for humans to hit the market in 25 years and has shown some utility in animal models.¹⁵ It is a mu agonist and norepinephrine reuptake inhibitor.

A sustained-release injectable buprenorphine is already on the market,¹⁶ although it is not an FDA-approved drug. Good evidence supports the use of other sustained-release opioids such as liposome-encapsulated hydromorphone,^17,18 but a commercial version is not on the horizon. However, several companies are pursuing long-acting opioid preparations or delivery mechanisms, and it is the expectation that the FDA will approve one or more in the not-too-distant future.

Novel peripherally acting mu-opioid receptor antagonists (PAMORAs) are being developed. When administered with an oral opioid, these drugs will permit central analgesia, while blocking their effect on gastrointestinal motility.^19,20

Several current drugs are being evaluated for their antiglial activity and may be available for use with opioids in the near future.²¹

Perhaps most intriguing is the investigation into genomics—how a specific opioid will act in a specific patient. With that information, medication choices and doses can be better tailored to the patient.²²

Mark E. Epstein, DVM, DABVP, CVPP
Carolinas Animal Pain Management
TotalBond Veterinary Hospital Forestbrook
3200 Union Road
Gastonia, NC 28056