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Cancer Pain Treatment

Opioids are commonly used for treating patients with cancer pain because of their safety, ease of titration, reliability, ease of administration and the effectiveness for all types of pains which include somatic, visceral, and neuropathic pain (1).

Morphine

Morphine is traditionally the prototype opioid drug that is used for severe cancer pain and thus serves as a standard for comparison (1). Many randomized trials and systematic reviews have failed to demonstrate the superiority of morphine over other mu agonists including hydromorphone, oxycodone, oxymorphone, fentanyl, or methadone in terms of tolerability or efficacy (2). Morphine binds to the mu receptors that are present in the inhibitory GABA-ergic neurons at sites such as the PAG in the CNS and prevents the release of GABA from the inhibitory neuron which will inhibit the ascending pain pathways and thus altering the perception and the response to pain (1,2). Morphine is metabolized in the liver and the metabolites are excreted renally (2). Because the metabolites which include morphine-6-glucuronide and morphine-3-glucuronide are associated with toxic effects, renal adjustments are required in patients that have renal impairment (2). If the Clcr is between 10-50 mL/min, 75% of the dose should be administered (3). The onset of action depends on the formulation used (1,2). Typically oral immediate release formulations have an onset of 30 minutes and duration of analgesic for 4 hours (3). Intravenous preparations have an onset of 5-10 minutes (3). The elimination half life for immediate release forms is 2-4 hours (3). Morphine is excreted through the urine primary as morphine-3-glucuronide (3).

The accumulation of morphine-6-glucuronide may cause toxicity associated with renal insufficiency (3). Side effects include circulatory depression, hypotension (>10%), drowsiness (9% to 48%), constipation (9-40%), urinary retention (16%), and atrial fibrillation (<3%) (3). Morphine may enhance the orthostatic hypotensive effect of thiazide diuretics and monitoring of blood pressure is necessary (3). Further monitoring parameters include pain relief, respiratory and mental status (3). For patients that take opioids chronically, there is a concern that the patient may become tolerant and require high doses than the usual dosing range to maintain the analgesic effect (2,3). This tolerance can be managed by appropriate dose titrations (2). For morphine in chronic pain, there is no optimal or maximal dose (1). The appropriate dose is individualized and is the dose that relieves the pain throughout the dosing interval without causing side effects that are unmanageable (1)

Hydromorphone may be useful in elderly patients and patients with renal dysfunction as opposed to morphine, which has an active metabolite that is renally excreted (4,5). This is because the active metabolites, which are the glucornidated molecules are present in much lower concentrations and will be less likely to cause adverse effects compared to morphine (4). Hydromorphone is a mu receptor agonist and acts in the same way as morphine (4). It binds to the opiate receptors in the CNS, which inhibits the ascending pain pathways, altering the perception and response to pain (4,5). Hydromorphone is more potent, more soluble and has better oral absorption properties that morphine, however the overall pharmacokinetic profile is parallel to morphine (1). The onset of action for oral formulates is 15-30 minutes and the peak effect occurs in 30-60 minutes (3). The duration of this effect lasts 4-5 minutes (3). The metabolism is through hepatic means via glucuronidation into inactive metabolites (3). The elimination is 2-3 hours (3). Adverse effects include vomiting, confusion, dizziness, drowsiness and constipation. In patients that have moderate renal impairment (Clcr = 40-60 mL/minute), a reduced dose should be started and the patient should be monitored closely (3). Monitoring endpoints include pain relief, mental and respiratory status and blood pressure (3). Because of the individual variation in response to different opiate agonists, it is recommended that the first few doses of oral hydromorphone to be reduced by ½ to 2/3 of the estimated equianalgesic dose (3). The dose of frequency of administration should then be adjusted based on the patient response (3). Hydromorphone may increase the orthostatic hypotensive effect of hydrochlorothiazide (3). Furthermore, hydromoprhone, which is a CNS depressant may enhance the adverse and toxic effects of other CNS depressants such as lorazepam (3). Thus symptoms of drowsiness, sedation, and respiratory depression should be monitored (3).

The dose conversion to hydromorphone from meperidine are as follows: 180 mg Po morphine in 24 hours is equal to 24-36 mg PO hydromorphone in 24 hours (3). Using a Q4H dosing interval, we want to prescribe 4-6 mg hydromorphone PO q4h (3). For breakthrough dosing, 40 mg morphine is used in 24 hours (3). This is equal to 5.3 mg hydromorphone per day, which is equal to 2.5 mg hydromorphone q1h PRN (3). Using another estimate, which is based on 10-15% of the total daily pain dosage on a q2-3h dosing, 0.4 to 0.9 mg hydromorphone should be used q2-3 hours (3) .

Meperidine

Meperidine is an agonist at the mu and an antagonist at the NMDA receptors(1,4). This medication is not ideal for chronic pain because it has a rapid onset (10-15 minutes orally) and very short duration of action (2 hours orally) (1,3). Therefore it is not recommended for chronic pain (1,3). In patients that have renal dysfunction, it can cause CNS toxicity with symptoms of seizures and tremors due to the accumulation of the toxic metabolite normeperidine (1,3). Therefore it is contraindicated in renal dysfunction as most of the drug is eliminated through the urine (1,3). This is not a viable recommendation for BH (1,3).

Codeine

Codeine is a weak opioid of the CNS (1). 60 mg of codeine produces similar analgesic effects to 600 mg of acetaminophen (3). It is converted to morphine by CYP2D6 (3). The onset of action occurs 30-60 minutes after oral administration and the duration of action is 4-6 hours (3). It is mainly excreted into the urine (3). Because of this, dosing adjustment for renal impairment is necessary (3). If the Clcr is between 10-50 mL/min, 75% of the dose should be administered (3). Chronic use of codeine leads to renal dysfunction due to the accumulation of toxic metabolites (4). Therefore, this is not the best recommendation for BH.

Fentanyl

Fentanyl is a highly lipophilic opioid that is used in transdermal and parental formulations for the management of pain. The transdermal formulation is used for managing chronic pain (1,6). The relatively infrequent dosing of the transdermal formulation (every 2 to 3 days) makes it an advantage for some patients (1,6). Two meta analyses have found a significant advantage for transdermal fentanyl over sustained release oral morphine in terms of constipation (6). This medication may also be preferred over morphine in patients that have renal insufficiency because of the lack of active metabolites (6). Exposing the patch to heat may increase the fentanyl absorption systematically which will increase the risk of respiratory depression (6). Fentanyl works by binding to stereospecific receptors at various sites within the CNS (6). It increases the pain threshold, alters the pain reception and increases the inhibition of the ascending pain pathways (6). The onset of action for the transdermal patch is 6 hours and the duration of action is 12 hours (6). Metabolism is through hepatic means primarily via CYP 3A4 (6). The elimination half life is 17 hours and excretion is 75% urine as metabolites (6).

Methadone

Methadone may cause an unpredictable half-life, possible excessive sedation, and difficulty in titration because with repeated doses the analgesic duration of action is prolonged (1,7). Methadone has unique properties as it also can antagonize the NMDA receptors and also has agonist effects at the kappa and delta receptors as well as blocking serotonin and norepinephrine reuptake (7). These properties have been beneficial in some patients who have chronic pain and in patients that have a maladaptive inflammatory component to their pain (7). One controlled found that methadone is equieffective to morphine in controlling cancer pain, but methadone is quite challenging to use (7). The half life is quite variable and it averages out to be 24 hours but can range to 12 hours to almost one week (7). Because of this, methadone has the highest risk among opioids of accumulation and overdosage during dose adjustment in chronic use (7). It can also prolong the QTc interval, which can predispose the patient to a life threatening cardiac arrhythmia, torsades du pointe (7). Therefore, this is not the best recommendation for BH (7).

References

  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 7th ed. Toronto: McGraw-Hill; 2007. P. 989-1003.
  2. Quigley C. Opioids in people with cancer-related pain. Clin Evid. 2008;1-16.
  3. Repchinsky C, editor. Codeine, Hydromorphone, Morphine, Meperidine. In: Compendium of Pharmaceuticals and Specialties [online version (e-CPS)]. Ottawa: Canadian Pharmacists Association; 2005 [cited 2012 Jan 27]. Available from: URL: http://e-cps.pharmacists.ca/CPHA/main.htm
  4. Jost L, Roila F. Management of cancer pain: ESMO Clinical Practice Guidelines. Annals of Oncology 2010;21(5):257-260.
  5. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage. 2003;25(2):169.
  6. Wong JO, Chiu GL, Tsao CJ, Chang CL. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Acta Anesthesiol Sin. 1997;32:25-32.
  7. Bryson J, Tamber A, Seccareccia D, Zimmermann. Methadone for treatment of cancer pain. Curr Oncol Rep. 2006;8(4):282.

Disclaimer

This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers


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