“The greatest enemy of knowledge is not ignorance; it is the illusion of knowledge.” Stephen Hawking
Opioids have undesirable side effects. Treating or preventing the side effects without “reversing” the desired effects is a holy grail. Undesirable side effects include: hypotension, hypertension, respiratory depression, apnea, bradycardia, tachycardia, skeletal muscle rigidity, hypothermia, and hyperthermia.
The classic opioid receptor types are: mu, (μ, MOR, OP3), kappa (κ, KOR, OP1), and delta (δ, DOR, OP2). Sigma (σ) receptors used to be considered opioid, but are not any longer. Epsilon (ε) is argued about. There is little agreement regarding the classification of opioid receptor subtypes. Opioid receptors belong to the G protein-coupled receptor family.
Agonists (mu) are: morphine, fentanyl, etorphine, carfentanil, A3080. A partial mu agonist is buprenorphine.
Antagonists are: naloxone, naltrexone, nalmephene, nalorphine, diprenorphine, levallorphan. The latter three, nalorphine, diprenorphine, and levallorphan, are older drugs; if they were discovered now, they would most likely be put into the next category.
Agonist/antagonists are: pentazocine, nalbuphine, and butorphanol. The dogma is that these are mu antagonists and kappa agonists. The anti-dogma is that butorphanol may be a partial mu agonist.2,5 It can be a mu agonist or antagonist depending on the circumstances!5
Opioid Receptor Effects and Interactions5
Lower efficacy opioids must bind to more receptors than higher efficacy opioids to produce a given effect. Different effects of a drug also depend on activation of different numbers of receptors, which can be altered by changing various parameters of the task, such as the intensity of the nociceptive stimulus in antinociceptive procedures. When the intensity is increased, the potency of any drug will decrease as more receptors must be occupied, and there will be a point at which drugs that must bind to a large proportion of receptors (i.e., lower efficacy drugs) cannot occupy enough receptors to produce a given effect. In these situations, lower efficacy opioids produce antinociception using low-intensity stimuli but fail to produce antinociception using high-intensity stimuli. Thus, there is an interaction between the intrinsic efficacy of an opioid and the stimulus intensity (or the efficacy requirement of the task) in producing antinociception. Studies have examined the interactions among opioids with varying degrees of intrinsic efficacy in cases in which the lower efficacy opioid fails to produce antinociception on its own. In these instances, the lower efficacy opioid competitively antagonizes the effects of higher efficacy opioids. This is the exciting anti-dogma, relating the observations that when low efficacy opioids for a given effect are given after a high efficacy drug for that effect, the low efficacy drug will “reverse” the effect, instead of producing it.
Combining Opioids to Improve Analgesia
Using Opioid Antagonists or Agonist/Antagonists to Reverse All the Effects of a Mu Agonist
Using antagonists is commonly done. Using agonist/antagonists is less common. We did this for many years, in dogs and cats, using nalbuphine (100 µg/kg i.v.).
Combining Opioids to Minimize Side Effects While Preserving Desired Effects
There is a great need to be able to do this consistently and safely with mu agonists and opioid antagonists or agonist/antagonists. We commonly do this in dogs and cats to treat opioid induced dysphoria or respiratory depression, with low doses of naloxone (2.5–10 µg/kg i.v.) or butorphanol (50 µg/kg i.v.).
This can be done in white rhinoceroses. In the white rhinoceroses partial reversal with diprenorphine or nalorphine is possible. This may be done to improve the oxygen saturation, or to get the animal up to allow it to walk to a desired location, or to reverse other negative effects. There is residual sedation for 6–8 hr.7 This use has also been reported in the wapiti.6 The next two presentations will be new reports of the use of butorphanol for reversal of mu-mediated side effects.
These are very exciting, useful drug interactions; however, the technique is not perfect and may be drug and species specific. In white rhinoceroses, the reversal with naltrexone is complete (at the doses used) and should only be used at these doses, when the desired effect is complete reversal (e.g., after immobilization for treatment).7 There is a report in humans of a study where nalbuphine was used to reverse respiratory depression from high dose fentanyl, while attempting to maintain analgesia, in which the study was cancelled after four patients because all four patients had serious side effects and also required additional pain therapy.1
1. Blaise, G.A., M. Nugent, J.C. McMichan, and P.A.C. Durant. 1990. Side effects of nalbuphine while reversing opioid-induced respiratory depression. Can. J. Anaesth. 37: 794–797.
2. Garner, H.R., T.F. Burke, C.D. Lawhorn, J.M. Stoner, and W. D. Wessinger. 1997. Butorphanol-mediated antinociception in mice: partial agonist effects and mu receptor involvement. JPET. 282: 1253–1261.
3. Gutstein, H.B., and H. Akil. 2001. Opioid analgesics. In: Hardman, J.G., L.E. Limbird and Gilman A.G. (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill, New York. 573–575, 578–579, 599, 601–604.
4. Lambert, D.G. 1998. Recent advances in opioid pharmacology: editorial. Br. J. Anaesth. 81: 1–2.
5. Morgan, D., C.D. Cook, M.A. Smith, and M.J. Picker. 1999. An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity. Anesth. Analg. 88: 407–413.
6. Moresco, A., R.S. Larsen, J.M. Sleeman, M.A. Wild, and J.S. Gaynor. 2001. Use of naloxone to reverse carfentanil citrate-induced hypoxemia and cardiopulmonary depression in rocky mountain wapiti (Cervus elaphus nelsoni). J. Zoo Wildl. Med. 32: 81–89.
7. Rogers, P.S. 1993. Chemical capture of the white rhinoceros (Ceratotherium simum). In: McKenzie, A.A. (ed.). The Capture and Care Manual, Wildlife Decision Support Services CC, Lynnwood Ridge, South Africa, and the South African Veterinary Foundation, Menlo Park, South Africa. 514–516, 523, 555.