Opioid analgesics

opioid analgesic  any of a class of compounds that bind with the opioid receptors in the central nervous system to block the perception of pain or affect the emotional response to pain, including opium and its derivatives.


Opioids are among the world's oldest known drugs; the use of the opium poppy for its therapeutic benefits predates recorded history. The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance.


Opioid Therapy:

Opioids are the most powerful analgesics available, with actions at peripheral, spinal and supraspinal levels. There are 4 types of opioid receptors, with multiple receptor subtypes. Mu receptors produce the most profound analgesia, and can cause euphoria, respiratory depression, physical dependence and bradycardia. Kappa receptors trigger a lesser analgesic response, and may cause miosis, sedation and dysphoria. Delta receptors modulate mu receptor activity. Sigma receptors provide little to no analgesia. They are responsible for many of the adverse effects associated with opioids (dysphoria, hallucinations, respiratory and vasomotor stimulation). Some investigators classify sigma receptors as phencyclidine, rather than opioid, receptors. Opioids can act asagonists (bind and stimulate receptors), antagonists (bind and block or inhibit activity),  partial agonists (bind and stimulate, but with less than full activity at certain receptor subtypes), and mixed agonist/antagonists (stimulating some receptors while blocking others). Opioids are useful in a variety of chronically painful conditions (though they may have limited effectiveness in some forms of neuropathic pain). For the purposes of chronic pain management, only the oral and transdermal versions of various opioids will be considered in the following discussion. Pure mu agonists provide the best analgesia, but also have the potential to produce the most side effects (bradycardia, hypotension, sedation, respiratory depression, urinary retention, vomiting, defecation, constipation). Their use is best limited to short-term “rescue” analgesia, though certain disorders (especially cancer pain) may require continual usage in the later stages of the disease. With chronic use, tolerance often develops, necessitating progressively higher doses to achieve an analgesic effect.  Morphine sulfate (CII) is available in oral tablet, capsule and liquid preparations. A suggested dose range in dogs is 0.5-2.0 mg/kg QID (some dogs experience unacceptable constipation at doses exceeding 1 mg/kg). Cats have been dosed with the liquid form at 0.2-0.5 mg/kg TID-QID, but most cats strongly dislike the taste.  Codeine has also been used as an oral mu agonist, though it is usually less efficacious than morphine due to the fact that dogs generally lack the CYP450 isoenzyme required to metabolize codeine to morphine. It is most commonly available in combination with acetaminophen as a CIII preparation, and is generally dosed in dogs at 1-2 mg/kg of the codeine portion TID-QID (acetaminophen should NOT be used in cats due to the risk of fatal methemoglobinemia). Fentanyl is available as a transdermal patch (Duragesic -- CII) in 25, 50, 75 and 100 ug/hour strengths. Some studies  suggest the 75 and 100 ug patches may not provide consistent plasma levels; combinations of 25 and 50 ug patches can be used to achieve the appropriate dose (2-4 ug/kg) in dogs. In cats > 2.5 kg, a whole 25 ug patch is used; if < 2.5 kg, half of the plastic backing covering the gel is removed (DO NOT CUT patches). Fentanyl patches can provide very good background analgesia, though they fail to provide adequate analgesia for some patients requiring supplemental oral mu agonists and the patch may fail to deliver any detectable fentanyl blood levels  for some patients . In dogs, the onset time is 12-36 hours, with a 72 hour duration of effect. Cats tend to have a faster onset time (5-8 hours) and a longer (up to 120 hours) duration. Side effects may include inappetance, agitation/dysphoria, sedation and hyperthermia (cats). Partial mu agonists bind at the mu receptors but only partially activate them. Buprenorphine (CIII) is the prototypical drug  in this class; it’s moderately expensive but VERY safe, producing few side effects and minimal sedation. Buprenorphine has tremendous affinity for the mu receptors, and will competitively inhibit pure mu agonists from binding. This property makes it useful for “reversing” the effects of morphine or fentanyl if adverse consequences arise, while still maintaining a level of analgesia. A ceiling effect on analgesia exists with partial agonists, making them less useful for severe pain. Buprenorphine is interesting in that increasing the dose prolongs the duration of analgesia, while the degree of pain relief remains essentially unchanged. Doses of 30 ug/kg (0.030 mg/kg) will provide ~ 8-10 hours of analgesia, and 40 ug/kg (0.040 mg/kg) may produce as much  as 12 hours of pain control. The onset of action is fairly slow (~ 30 minutes when given IV, 60 minutes IM, transmucosal or transdermal). Buprenorphine is not available as an oral preparation (it should not be compounded into an oral prep as significant  first-pass effect renders it inactive), but its lipophilic nature lends itself to absorption across skin or mucous membranes. Compounding pharmacies can produce a PLO (pleuronic lecithin organogel, or transdermal gel) for application on the inner surface of the pinna or shaved skin on the neck in dogs and cats. Alternatively, the alkaline salivary pH of cats allows for excellent transmucosal absorption when the injectable drug is given in the mouth (it should not be mixed with flavored syrups, as swallowing will inactivate it; the injectable form is tasteless and well-tolerated by cats). No studies have been performed on transmucosal usage in dogs, though the pH of their saliva is closer to that of humans, where bioavailability after mucosal administration is only ~ 30%. Mixed agonist/antagonists like butorphanol (CIV) are not considered useful in the management of chronic pain. First-pass effect destroys some of the drug, and the analgesia is considered to be relatively short-lived (1-2 hours). Because these drugs are kappa agonists and mu antagonists, the pain relief is often less than optimal for chronic discomfort. However, visceral nociception is considered to be more responsive to kappa agonism, leading some urologists to advocate butorphanol’s use in chronic bladder pain (FLUTD). Tramadol is one of the most useful drugs available to veterinarians for treating chronic pain. It has a dual mode of action: mu agonism (though it’s not technically an opioid, and is not a controlled substance) and monoamine reuptake inhibition (principally serotonin and norepinephrine), which enhances the endogenous spinal inhibitory mechanisms and produces mild anti-anxiety effects.  The degree of mu agonism produced is relatively weak (the parent compound has very little affinity for the mu receptors; most of the mu effects come from the M1 metabolite). However, in conjunction with the monoamine reuptake inhibition a powerful synergistic action occurs, leading to analgesia comparable to meperidine or codeine. It is helpful in a variety of acute and chronic pain syndromes, including neuropathic pain and allodynia. Combining tramadol with other analgesics (NSAID’s, mu agonists) further enhances tramadol’s efficacy, producing a multimodal pain relieving action. Because of tramadol’s monoamine reuptake inhibition, it should not be given with TCAs, SSRIs, or MAO inhibitors due to the risk of serotonin syndrome. In dogs, a starting dose of 3-5 mg/kg TID (up to 5 mg/kg QID) works well, though higher dose (10 mg/kg TID-QID) can be used if needed. Cats are dosed at 2-4 mg/kg (generally ¼ of a 50 mg tablet) BID. Metabolism is principally via hepatic biotransformation, with a small amount excreted unchanged by the kidneys. Side effects, though rare, may include GI upset and sedation.