Sheep model helps guide investigation of analgesia tolerance and reversal during opioid crisis

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reversal during opioid crisisHaving been honoured with the Best Basic Science Abstract Award at the North American Neuromodulation Society’s (NANS) 2020 annual meeting (23–26 January, Las Vegas, USA), Denise Wilkes now speaks to NeuroNews about how the perception of opioid treatment has changed over the past decade, and the benefits of using a large animal model to investigate analgesia tolerance and reversal.

Could you tell us about the rationale behind your study?

Overall, the rationale was to compare the rate of tolerance formation between an ultra-low dose or microdose intrathecal (IT) infusion, with 1mg/day—an intermediate dose—and 3mg morphine representing a standard higher dose.

How has the perception regarding the use of opioids (as a treatment) changed within the field in recent years?

We have had huge changes in our perception of opioids. Around 10–15 years ago we thought that tolerance, so heavily studied in rat models, was not much of a problem clinically. If patients developed tolerance, the dose would simply be increased. Now, during the opioid crisis, we are trying to limit prescribed amounts because of overdose risks, pharmacy availability, and prescriber pill counts totals. There are many incentives to use the minimal dose.

How should IT opioid therapy be initiated?

Chronic pain patients on long-term opioid therapy are often transitioned to intrathecal (IT) opioid route in order to improve analgesia. The method of transitioning patients from systemic to intrathecal delivery has considerable variation among physicians. A survey showed 40% wean, 33% did not wean, while starting doses varied from 12.5 μg/day to 1–2 mg/day.1,2,3 Microdose method is comprised of three phases: weaning of systemic opioids, an opioid-free period (4–6 weeks), and followed by an IT microdose morphine dose (less than 1 mg/day).4,5

What are the benefits of using a sheep model?

The sheep model has a dose response curve that is much closer to opioid effects observed in humans, enabling measurement of effects of dose, duration of dose, and discontinuation. The size of the sheep allows us to be able to use commercially available devises such as IT infusion pumps.

What did you find regarding the morphine dose-response?

Morphine tolerance is best measured by a change in slope of the morphine dose-response curve from pre- to post-infusions. We showed that there was a greater reduction in the slope with the 3mg/day than the 1mg/day. There was negligible development of tolerance with the microdose, or 0.2mg/day.

Did you draw any further conclusions from the results?

It is important to keep opioid doses low. A higher dose will create more tolerance and then the opioids will be even less effective. We need to supplement medical management with interventions that can reduce pain even if it is only relatively short-lived.

What do future studies need to take into account?

Future studies need to examine bolus doing and other infusion methods, while the systemic effects of microdose IT therapy also warrant further investigation. We initially thought that IT mostly avoided these effects but high dose IT does produce systemic side-effects. Unfortunately, those doses were high and we do not know what is the threshold.

References

  1. Deer TR, Prager J, Levy R, Burton A, Buchser E, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs M, Kim P, Kumar K, Leong M, Liem L, McDowell G, Panchal SJ, Rauck R, Saulino M, Staats P, Stanton-Hicks M, Stearns L, Sitzman BT, Wallace M, Willis KD, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference–2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 2012:15: 420-435; discussion 435.
  2. Deer TR, Prager J, Levy R, Rathmell J, Buchser E, Burton A, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs MS, Kim P, Kumar K, Leong M, Liem L, McDowell GC, 2nd, Panchal S, Rauck R, Saulino M, Sitzman BT, Staats P, Stanton-Hicks M, Stearns L, Wallace M, Willis KD, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 2012:15: 436-464; discussion 464-436.
  3. Wilkes DM, Orillosa SJ, Hustak EC, Williams CG, Doulatram GR, Solanki DR, Garcia EA, Huang L-YM. Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics. Pain Medicine 2017.
  4. Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, Soteropoulos C, Barreto J, Deschner S, Ketchum J. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med 2012:13: 1304-1313.
  5. Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician 2011:14: 343-35

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