Opioids: Why should poppies be so popular? (Proceedings)

Opioids are a group of natural derivatives or synthetic relatives of opium, which is extracted from the exudate of seedpods of the opium poppy, Papaver somniferum. The poppy plant appears to have been cultivated in ancient civilizations, like those of Persia, Egypt and Mesopotamia, and the first known written reference to the poppy appears in 4,000 BC (from 'A Brief History of Opium' at http://opiates.net).

Both the recreational and the medical attributes of opioids were well known throughout history and the compounds were widely used in all levels of society and opium was easily obtained from the local druggist. Crude opium was the main form of the drug until 1805 when morphine was isolated from opium by a German pharmacist, who named it morphium - after Morpheus, the Greek god of dreams (from 'A Brief History of Opium' at http://opiates.net). Today there are numerous forms of the drug and numerous medical applications. There is also extensive interest in the drug class and a 2011 PubMed search of 'opioids' yielded 110,814 hits.

Opioids bind to specific opioid receptors that are located primarily in the central and peripheral nervous systems, although locations exist in other tissues (eg, synovium). The three principal opioid receptors are mu, kappa and delta, and numerous other minor receptors and subreceptors have been identified. Opioids primarily bind to presynaptic receptors and cause a decrease in the release of excitatory neurotransmitters.

Opioids are traditionally (and loosely) classified as 'full agonists', 'partial agonists', 'agonists-antagonists' and 'antagonists', depending on their activity at the mu opioid receptor. Full agonists bind to and activate both the mu and kappa receptors and commonly used drugs in this category include morphine, hydromorphone, fentanyl (and the fentanyl derivatives), methadone and codeine. Partial agonists bind to, but only partially activate, the mu receptor and can have varying activity at the kappa receptor. The drug most commonly used in veterinary medicine that fits this category is buprenorphine. Some experts consider buprenorphine to be an agonist-antagonist but most feel that it better fits the partial agonist category. The classically used agonist-antagonist is butorphanol, which is an agonist at the kappa receptor but an antagonist at the mu receptor. Pentazocine and nalbuphine are also agonist-antagonists. Finally, we have the antagonists, naloxone and naltrexone. Antagonists bind to the receptor but do not activate it. The binding blocks the binding of the drugs that would activate the receptor (the agonists), thereby eliminating the effects of those drugs.

Opioids are a versatile class of drugs that can be used systemically (IV, IM, SQ, PO), in the epidural or intrathecal space and in the articular space. Opioids can be used to treat both acute (Table 1) and chronic (Table 2) pain. The primary medically positive effect of opioids is analgesia, although euphoria may also be considered a benefit in certain patients. The primary medically adverse effects of the opioids include nausea, vomiting, constipation, slowing of GI motility, dysphoria, pruritis and respiratory depression. The actual incidence of many of these side effects is highly overstated and the benefits of the opioid class should be weighed against the potential for the adverse effects.

Table 1: Guidelines and dosages for using opioids for acute pain in dogs and cats

Opioids are THE MOST POTENT class of analgesic drugs available and should be utilized anytime that pain occurs – especially if pain is moderate to severe.

     • Advantages: Provide moderate to profound analgesia, safe, reversible, many are inexpensive, provide sedation, versatile (can be administered PO, IM, IV, SQ, in the epidural space, in the intra-articular space, etc…)

     • Disadvantages: may not provide enough sedation when used alone in young, healthy or excited patients; not all opioids are sedating in cats; short duration of action when compared to the duration of pain from most procedures or injuries.

          o NOTE: Opioid-induced respiratory depression is HIGHLY OVERRATED. In animals, respiratory depression is almost always directly related to degree of sedation - in which case, ALL sedatives are respiratory depressants.

     • Full agonists (morphine, hydromorphone, oxymorphone, fentanyl)

          o Most potent class of analgesic drugs

          o Should be considered any time that pain is moderate to severe

          o Excellent premedicants since they provide analgesia and sedation

          o Time to onset - < 5mins (< 1 min when administered IV)

          o Duration of action 4-6 hours (oxymorphone closest to 6 hrs; approx 4 hours for morphine and hydromorphone)

          o Uses: IV (morphine not generally bolused IV), IM, SQ, transdermal patch (fentanyl), CRI, epidural space, intra-articular space, etc…

          o Effects

               • Sedation - beneficial effect pre-op and often post-op

               • Vomiting - beneficial effect when used pre-op, empties stomach

               • Respiratory depression? Not a major concern like it is in human beings; directly related to degree of sedation.

               • Cardiovascular depression? Very minor, opioids are extremely safe for patients with cardiovascular disease.

          o Recommendation: In dogs, use a full agonist opioid as your standard opioid, use other opioids in the rare instance when a full opioid isn't the best choice.

          o Recommendation: Don't be afraid to use a full opioid agonist in cats – just use a touch of ace or medetomidine with the opioid.

          o Dog Dosages:

               • Morphine 0.25-1.0 mg/kg IM (0.25 for geriatrics, 0.5 soft tissue, 1.0 orthopedics)

               • Hydromorphone 0.1-0.2 mg/kg IM, IV, SQ

               • Fentanyl 0.001-0.005 mg/kg IV (can be administered IM or SQ)

          o Cat Dosages:

               • Morphine 0.1-0.25 mg/kg IM

               • Hydromorphone 0.1 mg/kg IM, IV, SQ

               • Fentanyl 0.001-0.005 mg/kg IV (can be administered IM or SQ)

     • Partial agonists (buprenorphine), agonist-antagonists (butorphanol)

          o Not as potent as the full agonist class

               • Don't confuse binding potency with analgesic potency

          o Should be considered when pain is mild to moderate

          o May not be potent enough nor have a long enough duration (butorphanol) to be used alone as a premedicant for many of our surgical procedures. Use as part of a multimodal protocol.

          o Time to onset - < 5 mins (butorphanol); 10-20 mins (buprenorphine)

          o Duration of action - 45-90 mins (butorphanol); 6-12 hours (buprenorphine)

          o Uses: IV, IM, SQ, transmucosal (buprenorphine), CRI? (butorphanol, not as effective as full agonist CRIs)

          o Effects

               • Similar to the effects of full agonists but not as pronounced

               • Butorphanol provides moderate sedation, buprenorphine generally provides mild to no sedation (can be sedating at higher dosages).

          o Recommendation: Use buprenorphine bucally in cats, both in-hospital and for at-home therapy. Use butorphanol as a sedative in cats – alone or with midazolam in old or debilitated patients or with an alpha-2 agonist in young, healthy patients. Then add buprenorphine for longer duration of analgesia.

          o Dog and Cat Dosages:

               • Buprenorphine 0.01-0.03 mg/kg IM, IV, SQ, buccal (transmucosal)

               • Butorphanol 0.2-0.4 mg/kg IM, IV, SQ

     • Other Opioids – Tramadol

          o 'Opioid-like' drug – portion of analgesia is mediated through opioid pathway

          o Other mechanisms of action include inhibition of serotonin re-uptake

          o Advantages: Not DEA controlled, excellent addition to NSAIDs

          o Disadvantages: Absorption HIGHLY variable in the dog (65+/-38%). Use as part of a MULTIMODAL protocol. Higher percentage of absorption & formation of active metabolite in cats than in most other veterinary species. Highly likely to cause dysphoria but may cause sedation in cats, commonly causes sedation in dogs. May cause decreased appetite and constipation (generally only at higher dosages), may cause seizures in dogs (RARE) – not reported in the cat.

          o Recommendation: Use as part of multimodal therapy in most species

          o Dog Dosage: 2-5 mg/kg BID to QID

          o Cat Dosage: Not clear, 1-4 mg/kg PO BID?

Table 2: Opioids used to treat chronic pain in dogs and cats.