PERT Program

Tip of the Month: November 2005


TREATMENT OF OPIOID-INDUCED SEDATION


Sedation is a common transient side effect when initiating therapy or increasing doses. In some cases, persistent and undesirable sedation occurs, causing distress for patients and families, as well as reluctance by staff to give opioids. This can result in undertreatment of pain. There are a number of strategies to manage opioid-induced sedation. Because there is such a significant individual variability in how patients respond to opioids, a switch to a different opioid may eliminate this bothersome side effect. Another approach to managing opioid-induced sedation is to add a stimulant medication. Often the addition of the stimulating medication will counteract the sedation and allow for continued optimal use of the opioid.

Reissig and Rybarcek recently reviewed the literature on treatment of opioid-induced sedation.1 These authors examined all studies from 1996 through 2003 for five pharmacologic treatments of opioid-induced sedation: caffeine, methylphenidate (Ritalin®), dextroamphetamine (Adderall®), modafinil (Provigil®), and donepezil (Aricept®).

The authors noted that the studies had many methodological weaknesses — most were retrospective chart audits and case studies. There were a few controlled trials with small sample sizes. Based on the available evidence, they concluded that methylphenidate and dextroamphetamine should be considered first line therapy for the treatment of opioid-induced sedation, while modafinil and donepezil are also promising treatments.

Methylphenidate (Ritalin®)is the most widely studied and discussed stimulant in the palliative care literature. It has clearly been demonstrated to reduce drowsiness in cancer patients receiving opioids.2-6 In general, it is best to start with a 2.5 mg dose (half of a 5 mg tablet) in the early AM for several days to evaluate for any side effects. If there are no side effects, the AM dose can be elevated to 5 mg and the dose increased by 2.5 mg every 5 to 7 days to a dose of 10–15 mg. A second dose at noon is often needed to maintain effect later in the day. A typical schedule is 10 mg at 8AM and 5 mg at noon. Dose range is up to 30 mg. In some patients a tolerance to the stimulating effect of methylphenidate can occur over time.

Methylphenidate has also been studied and shown to reduce both fatigue7 and depression.8 These additional potential benefits add to the evidence supporting methylphenidate as a good choice for palliative care. There are side effects, however, that can be problematic. Some patients experience side effects such as insomnia, nervousness, palpitations, hallucinations, and tachycardia. These effects are generally dose-related. Methylphenidate is contraindicated in patients with psychiatric disorders (particularly delirium) as well as uncontrolled cardiac arrhythmias (particularly paroxysmal tachyarrythmias).8,9

Dextroamphetamine (Adderall®), like methylphenidate, blocks the reuptake of norepinephrine and dopamine in the central nervous system to increase alertness and has been shown to reduce drowsiness in opioid-induced sedation.10,11 Dosing starts at 2.5 mg in the early AM and ranges up to 30 mg per day, utilizing either morning and midday doses of the short-acting formulation, or one-time dosing in the morning of the long acting formulation. Patients who do not respond well to methylphenidate, or have become tolerant to the effects of the methylphenidate, may benefit from a trial of dextroamphetamine. Primary side effects are similar to methylphenidate, consisting most commonly of jitteriness and insomnia.

Caffeine is a readily available stimulant with a structure similar to theophylline that acts through blockage of the methylxanthine-sensitive adenosine receptors. A recent review article underscored the lack of well-designed studies on caffeine for opioid-induced sedation, but went on to anecdotally propose a dose range of 200 mg up to four times a day for treatment of opioid-induced sedation in cancer patients.12 Caffeine is known to induce stimulation of the heart and increase gastric acid secretion. Most common side effects are mild agitation, palpitations, and dyspepsia.

Modafinil (Provigil®) is a non-amphetamine stimulant whose mechanism of action is not completely understood. It is FDA-approved for the treatment of narcolepsy. A limited amount of data exists for use of the drug in opioid-induced sedation.13,14 There may be less jitteriness or anxiety with this agent than with traditional stimulants. Dosing begins at 100 mg in the AM and can be increased to 200 mg.

Donepezil has recently been identified as an effective treatment for opioid induced sedation.15,16 This agent, developed for treatment of Alzheimers, is an anticholinesterase inhibitor that is believed to counter opioid-induced reduction of acetylcholine in the brain. Starting dose is 2.5 mg in the morning with gradual increases to 5 mg in the morning and 5 mg at midday.

Opioid-induced sedation can be a road block to optimal pain and symptom management. Pharmacologic treatment with stimulating medications is one method to reverse this problem. Starting with a low dose and carefully titrating up the dose is the primary principle of treatment. Utilizing methylphenidate or dextroamphetamine as first line agents is supported in the literature, while other agents such as modafinil and donepezil may offer alternative choices that can be used by the palliative care team.



Summary of Stimulating Medication
Agents Starting Dose Titrating Schedule Typical Schedule Max Dose
Methylphenidate (Ritalin®) 2.5 mg in early AM Add 2.5 mg at early AM or midday dose every 5–7 days 10 mg at 8AM
5 mg at noon		 30 mg/day
Dextroamphetamine(Adderall®) 2.5 mg in early AM Add 2.5 mg every 5–7 days in divided doses for short-acting, or AM dose only for long-acting form 20 mg of long-acting form at 8AM 20 mg/day
Caffeine 200 mg in early AM Increase by 200 mg up to 200 mg QID as tolerated 200 mg at 8AM and noon 800 mg/day
Modafinil (Provigil®) 100 mg in early AM Increase to 200 mg in AM in 5–7 days 200 mg at 8AM 200 mg/day





This month's tip was prepared by Anna Du Pen, ARNP, MN. If you have questions or comments about this article, you can reach the author via the PERT Program contact page.



References

  1. Reissig JE, Rybarczyk AM: Pharmacologic treatment of opioid-induced sedation in chronic pain. Annals of Pharmacotherapy 39(4): 727-731, 2005.
  2. Bruera E, Miller MJ, MacMillan K, et al: Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 48;163-166, 1992.
  3. Wilberding MB, Loiprinzi CL, Mailliard JA, et al: A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics. Support Care Cancer 3;135-138, 1995.
  4. Bruera E, Chadwick S, Brenneis C, et al: Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep 71:67-70, 1987.
  5. Bruera E, Brenneis C, Paterson A, et al: Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. Journal of Pain and Symptom Management 4:3-6, 1989.
  6. Bruera E, Fainsinger R, MacEachern T: The use of methylphenidate in patients with incident cancer pain receiving regular opiates: A preliminary report. Pain 50:75-77, 1992.
  7. Bruera E, Driver L, Barnes EA, et al: Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: A preliminary report. Journal of Clinical Oncology 21(23):4439-4443, 2003.
  8. Hajra L: Use of methylphenidate for treatment of depression in cancer patients: A literature review. University of Toronto Medical Journal 82(1):10-11, 2004
  9. Cherny N, Ripamonti C, Pereira J, et al.: Strategies to manage the adverse effects of oral morphine: An evidence based report. Journal of Clinical Oncology 19(9):2542-2554, 2001.
  10. Kreeger L, Duncan A, Cowap J. Psychostimulants used for opioid induced drowsiness. Journal of Pain and Symptom Management 11:1-2, 1996.
  11. Yee JD, Berde CB: Dextroamphetamine or methylphenidate as adjuvants to opioid analagesia for adolescents with cancer. Journal of Pain and Symptom Management 9:122-125, 1994.
  12. Manfredi P, Gonzales G: Symptomatic uses of caffeine in patients with cancer. Journal of Palliative Care 19(1):63-65, 2003.
  13. Webster L, Andrews M, Stoddard G: Modafinil treatment of opioid induced sedation. Pain Medicine 4(2):135-140, 2003.
  14. Jensen MG, Sorensen R: Modafinil for excessive daytime sleepiness secondary to opiates and adjunctive pain medications: a case report. The Pain Clinic: A Multidisciplinary Approach to Acute and Chronic Pain Management 6:5-8, 2004.
  15. Slatkin N, Rhiner M, Bolton T: Donepezil in the treatment of opioid-induced sedation - A report of six cases. Journal of Pain and Symptom Management 21(5):425-438, 2001.
  16. Bruera E, Strasser F, Shen L, et al: The effects of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: A pilot study. Journal of Pain and Symptom Management 26:1049-1054, 2003.