Tips for Clinicians

Opioids and Nausea (article one of two)

Author: David E. Weissman MD

Background: Why do patients get nauseated and vomit after receiving an opioid? Commonly described as an “allergy”, opioid-induced nausea/vomiting is not an allergic reaction. In fact, rather than indicating a pathologic reaction, nausea indicates normal functioning of the brain. Opioid-induced nausea occurs through the following mechanisms:

• At the base of the 4th ventricle lies the chemoreceptor trigger zone (CTZ), a “sampling port”, to detect substances that do not belong in the blood. Adjacent
  to the CTZ lies the medullary vomiting center which controls the complex
  muscular sequence of vomiting. When the CTZ detects a noxious chemical in the blood, a signal is sent to the VC and the vomiting reflex is initiated. Of note,
  this is the same mechanism when patients vomit after receiving chemotherapy.

• Opioids can directly stimulate the vestibular apparatus-patients note a spinning sensation with their nausea.

• Opioids cause constipation which can lead to nausea via stimulation of afferent cholinergic pathways.

Do all opioids produce the same degree of nausea? There is little research on this topic. In clinical practice, morphine and codeine are often mentioned as the worst offenders.

Why are some patients more sensitive to the emetic effects of opioids than others? Unknown.

What is the natural history of opioid-induced nausea? Most patients develop tolerance to the emetic effects, so that within 7-10 days, at a constant opioid dose,
the emetic effect will abate.

What are management approaches?

• Dose adjustment – if good pain relief is achieved but associated with nausea,
  it may be possible to lower the opioid dose, still retain good analgesia, but eliminate the nausea.

• Switching opioids – There is variability in emetic reaction to different opioids. Note: since tolerance to nausea develops, one never knows if reduction in
  nausea is from the change of drug or tolerance.

• Anti-emetics – Whenever possible, choose a drug directed at the most likely cause of nausea. There is little published data to guide physicians in specific
  choice of anti-emetic for opioid-induced nausea.

• Start with low-cost dopamine antagonists (e.g. prochlorperazine) or anti-cholinergics (e.g. scopolamine)

• Anti-histamines may be helpful for patients who note a spinning sensation.

• 5HT3 antagonists (e.g. ondansetron) can be used for refractory cases. Two multi-center randomized trials have examined control of emesis associated with opioids not used for anesthesia. In one, 16 mg of ondansetron was more effective than 8 mg or placebo. In the other trial, stopped early due to lack of patient accrual, 24 mg ondansetron was no better than placebo or metoclopramide.

• Non-pharmacological approaches: there is little evidence to support non-pharmacological treatments for nausea outside of chemotherapy associated nausea; suggested approaches include acupressure and behavioral treatments.

References:
1. Hardman JG, Limbird LE, et al, eds. Goodman’s and Gillman’s
The Pharmacological Basis of Therapeutics.
2. Herndon CM, et al. Management of Opioid-Induced Gastrointestinal Effectd in Patients Receiving Palliative Care.
3. Glare P, Support Care Cancer.
4. Hardy J, A study of opioid-induced nausea
5. Pan CX, Complementary and Alternative Medicine in the
Management of Pain, Dyspnea, Nausea and Vomiting.

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Controlled Release Oxycodone

Author: David E. Weissman, MD

Background: Controlled release oxycodone (CRO) has received considerable attention in the lay press over the past several years. Much of the coverage has been negative, related to the illicit use of CRO due to diversion outside of legitimate medical practice, CRO is an effective long acting oral opioid product, very similar to control released morphine. This article reviews CRO usage in palliative care.

Indication: CRO is indicated for moderate to severe pain requiring continuous, around the clock analgesia for an extended period of time.

Pharmacology: Oxycodone is a semi-synthetic opioid that interacts with both mu-and kappa-opioid receptors, but behaves in most respects identically to morphine. CRO has greater oral bioavailability than morphine, and a bi-phasic absorption pattern, with peaks at 37 minutes and 6.2 hours. Peak pain relief occurs in one hour. Unlike morphine, oxycodone has minimally active metabolites, demonstrating little to no analgesic or anti-analgesic properties. Oxycodone should be used with caution in patients with renal and liver impairment and avoided in in hemodialysis patients. CRO can lead to all the traditional opioid side effects. Anecdotal reports suggest less nausea and hallucinosis compared to morphine, although these observations have not been substantiated in controlled trials.

Equianalgesic Information: Studies comparing round the clock immediate release oxycodone to controlled release oxycodone products demonstrate equivalent results. The conversion factor between between morphine and oxycodone has been controversial, but the most commonly accepted data suggests that 30 mg of morphine is equivalent to 20 mg of oxycodone. Since all equianalgesic values are rough guidelines, prescribers need to use their clinical judgment in determining the most appropriate starting dose.

Dosage: The starting dose of CRO in an opioid naïve patient is 10 mg q 12 hours;
it can be dose escalated every 24 – 48 hours. CRO must be taken intact; pills cannot
be cut or crushed without risk of rapid absorption and subsequent overdose. CRO is
not approved for rectal administration.

Cost: CRO is more expensive than generic long-lasting morphine; there is currently no generic CRO on the market.

Diversion: CRO has been associated with greater diversion to the illicit drug market than morphine. Illicit users will commonly crush the tablet then chew, snort, or dissolve the product in water for intravenous injection. CRO can bring $1.00 per milligram or more on the illicit market.

Summary: CRO oxycodone is an effective long-acting oral opioid. Due to cost and concerns about diversion, controlled release morphine is the drug of first choice for a long- acting oral opioid product. There is not data that CRO offers any analgesic
benefit compared to morphine.

References:
1. Kral LA. Commonsense oxycodone prescribing and safety. Pain Treatment Topics.
2. Mucci-LoRusso p, Berman BS, Silberstein PT, et al. Controlled-release oxycodone compared with control-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel group study.
3. Principles of analgesic use in the treatment of acute pain and cancer pain. Glenview, IL: American Pain Society 5th ED.
4. Floral PA, Ineck JR, Nystrom KK. Oxycodone accumulation in a hemodialysis patient.
5. Rischitelli DG, Karbowicz SH. Safety and efficacy of controlled release oxycodone:
a systematic literature review.
6. SAMHSA (Substance Abuse and Mental Health Service Administration).
7. Criteria for use of Controlled Release Oxycodone: Treatment Algorithm. Veteran Affairs Pharmacy Benefits Management.

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