Medication Pearls For Practice: Methadone In Cancer Pain Overview

METHADONE

History2:

• Methadone was developed in Germany (it is synthesized from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy.
• The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-dol" or "-phine" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler, despite what Tom Cruise and the Church Of Scientology will have you believe.

Class1: Opioid analgesic.

Indications1:

• Moderate–severe pain (an alternative in cases of intolerance to other strong opioids, morphine poorly-responsive pain)
• pain relief in severe renal failure
• cough
• Also treatment of opioid addiction.

Potential uses1,3:

• Neuropathic pain (refractory)
• painful mouth ulcers: It has been used effectively as a mouthwash
• Restless Leg Syndrome: methadone (5 to 20 mg) have been administered in divided doses, 1 to 2 hours prior to bedtime.3

Pharmacology/Pharmacodynamics1:

• Methadone is a synthetic strong opioid with mixed properties. Thus, it is a μ-opioid receptor agonist, possibly a -opioid receptor agonist, an NMDA-receptor-channel blocker, and a presynaptic blocker of serotonin re-uptake.1
• Methadone binds to Mu (μ), Kappa (κ), and Delta (δ) opioid receptors, producing analgesia as well as typical opioid side effects.6 (See Notes section at end of document for opioid receptor information.
• There is no predictable relationship between methadone plasmalevel and pain relief.
• Methadone is a racemic mixture; L-methadone is responsible for most of the analgesic effect, whereas D-methadone is antitussive.
• Methadone is a non-acidic and lipophilic drug which is absorbed well from all routes of administration.

• Partly because of its lipid-solubility methadone has a high volume of distribution with only about 1% of the drug in the blood.
• Methadone accumulates in tissues when given repeatedly, creating an extensive reservoir.

Pharmacokinetics1:

• While methadone can be administered by a number of routes: oral, rectal, intravenous, intramuscular, subcutaneous, epidural, and intrathecal – it is most commonly given orally in either tablets or solution.
• Oral methadone is readily absorbed and very long-acting.
• By comparison, its bioavailability is nearly 3 times that of morphine and its half-life is about 10 times greater than morphine.6

• Bio-availability 80% (range 40–100%) PO.
• Onset of action <30min PO, 15min IM.
• Time to peak plasma concentration 4h PO; 1h IM.
• Plasma halflife 8–75h; longer in older patients; acidifying the urine results in a shorter halflife (20h) and raising the pH with sodium bicarbonate a longer halflife (>40h).

*methadone has an extended terminal half-life, up to 190 hours. This half-life does not match the observed duration of analgesia (6-12 hours) after steady state is reached. This long half-life can lead to increased risk for sedation and respiratory depression, especially in the elderly or with rapid dose adjustments.5

• Duration of action 4–5h PO and 3–5h IM single dose; 8–12h repeated doses.

Cautions:

In 2006, after a review of deaths and life-threatening adverse events (e.g. respiratory depression, cardiac arrhythmia) associated with unintentional overdose, drug interactions, and prolongation of the QT interval, the FDA in the USA issued a safety warning about the use of methadone. This highlighted the need for:

• physicians to be fully aware of the pharmacology of methadone
• close monitoring of the patient when starting methadone, particularly when switching from a high dose of another opioid
• slow dose titration, and close monitoring of the patient when changing the dose of methadone
• warning the patient not to exceed the prescribed dose.

Palliativedrugs.comconsiders that cumulation to a variable extent is bound to occur, particularly in elderly patients, and recommends p.r.n. dose titration to minimize the associated risk

Dosage:

• Dose titration is different from morphine because of the wide interindividual variation in the pharmacokinetics of methadone. Several guidelines exist for switching from morphine to methadone.
• Because of its long half life, plasma levels of methadone may take up to 10 days to stabilize. There must be a cautious balance between inadequate analgesia due to insufficient dosing and systemic toxicity due to excessive dose during the titration phase.6
• For detailed dosing guidelines: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• http://www.palliativedrugs.com/methadone.html#guidelines
• From Lexicomp4:

Acute pain (moderate-to-severe):

Opioid-naive: Oral: Initial: 2.5-10 mg every 8-12 hours; more frequent administration may be required during initiation to maintain adequate analgesia. Dosage interval may range from 4-12 hours, since duration of analgesia is relatively short during the first days of therapy, but increases substantially with continued administration.

Chronic pain (opioid-tolerant): Conversion from oral morphine to oral methadone:

• Daily oral morphine dose <100 mg: Estimated daily oral methadone dose*: 20% to 30% of total daily morphine dose
• Daily oral morphine dose 100-300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose
• Daily oral morphine dose 300-600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose
• Daily oral morphine dose 600-1000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.
• Daily oral morphine dose >1000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.
• *in divided doses (commonly q12h, q8h or q6h)

• Subsequent switching from methadone to other opioids can be difficult. In one series 12/13 patients experienced increased pain±dysphoria.1

Conversion:

• See: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• See: http://www.palliativedrugs.com/methadone.html#guidelines

Dose Adjustments1,6:

• Renal and hepatic impairment do not affect methadone clearance.
• When considering the use of methadone, the difficulty of subsequently switching from methadone to another opioid should also be borne in mind.
• Methadone is an alternative strong opioid for patients with chronic renal failure who would be at risk of excessive drowsiness±delirium with morphine because of cumulation of morphine-6-glucuronide.2
• Methadone is poorly removed by haemodialysis.30 However, for moribund patients, alfentanil is probably a better choice.
• Unlike morphine or meperidine, the metabolism of methadone produces no active or toxic metabolites.
• Only a minor fraction of methadone is cleared by the kidneys. Except in end-stage renal failure, it is usually unnecessary to adjust the dose of methadone because of renal disease.
• For patients with severe chronic liver disease, the elimination half-life of methadone increases. However, mean plasma concentrations and dose-adjusted mean plasma concentration do not significantly differ from patients with mild or moderate liver disease (Säwe, 1986), and no dose adjustments are typically required for this degree of hepatic failure (Eap, 2002).

Monitor:

• sedation
• confusion
• respiratory depression

Other Side Effects:

• lightheadedness, weakness
• dry mouth, urinary retention, constipation
• sleep apnea (see http://onco-prn.blogspot.com/2009/10/medication-pearls-for-practice.html )

Interactions1:

• Methadone is principally metabolized by CYP3A4
• CYP2D6, CYP2C9, CYP2C19 and CYP1A2 may play minor roles
• MAOIs may prolong and enhance the respiratory depressant effects of methadone.
• Carbamazepine, phenobarbital, phenytoin and rifampicin increase the metabolism of methadone
• amitriptyline, cimetidine, ciprofloxacin, fluconazole and SSRIs decrease its metabolism
• Methadone increases plasma zidovudine concentration.
• Efavirenz, lopinavir-ritonavir, nelfinavir, nevirapine and ritonavir (all antiretroviral agents) may reduce plasma methadone concentrations.
• Other medications, especially the benzodiazepines, may act synergistically with methadone, increasing the apparent effect of methadone and likelihood for life threatening adverse events.
• Certain medications may potentially influence the concentration of methadone indirectly. For example, topiramate is a carbonic anhydrase inhibitor and increases urinary pH alkalinization; Topamax PI 2007). Alkalinization of urine has been shown to increase the half-life of methadone to an average of 42 hours (Baselt 2004). Therefore, when used concomitantly with topiramate, methadone may reach higher plasma levels.
• Check: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
• Always check reliable drug interaction sources such as Lexicomp and Micromedex

Patient Handout:

• Great patient information (print page 4-5 of the document)

http://pain-topics.org/pdf/MethadoneHandout.pdf

Advantages:

• Inexpensive
• can use in patients with morphine allergy
• ok with renal patients
• generally less constipating
• more effective for neuropathic pain in comparison with other opioids
• suited for the management of difficult pain syndromes, particularly where activation of the NMDA recptors has resulted in CNS sensitization - hyperanalgesia and allodynia {Note: Without the d-isomer [racemic d- & l-isomer used in North America ] less impressive results may be observed.}

Interesting…

• 9th on list of most abused drugs in U.S. see: http://www.drugabuseclinic.org/methadone-abuse.html

Sources/References:

1. http://www.palliativedrugs.com/methadone.html
2. http://en.wikipedia.org/wiki/Methadone
3. Micromedex Online
4. Lexicomp Online
5. http://www.eperc.mcw.edu/FastFactPDF/Concept%20075.pdf
6. http://pain-topics.org/pdf/OralMethadoneDosing.pdf
7. Pallium Palliative Handbook 2008 www.pallium.ca

inical Effects

*NOTES:

Receptor > Clinical Effects:

• Mu (μ): Analgesia, Euphoria, Respiratory depression, Physical dependence, Miosis, Decreased gastric motility
• Kappa (κ ): Analgesia, Sedation, Respiratory depression
• Delta (δ): Analgesia, Dysphoria, Hallucinations

*Adapted from: Warfield and Fausett, 2002

*(one pt - I.R. – took 90 mg qid + 60 mg q2h for over 700 mg/day – max we’ve seen)

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Medications In The Pipeline: Intranasal Fentanyl Spray Versus Oral Transmucosal Fentanyl Citrate

A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial

Current Medical Research and Opinion, 10/08/09

“Mercadante S et al. – In this open–label, randomised, crossover trial, significantly more patients attained faster ‘meaningful’ pain relief with intranasal fentanyl spray (INFS) than oral transmucosal fentanyl citrate (OTFC), and more patients preferred INFS to OTFC.”

Results:

Among the intention-to-treat population (n ¼ 139):
• median time to onset of ‘meaningful’ pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to ‘meaningful’ pain-relief onset with INFS ( p50.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing.
• Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (_33% and _50% PI reduction) up to 30 minutes post-dosing.
• The proportions of episodes treated with INFS and OTFC achieving a PI reduction of _33% at 5 minutes were 25.3% versus 6.8% ( p50.001), and at 10 minutes were 51.0% versus 23.6% ( p50.001), respectively
• The proportions of episodes treated with INFS and OTFC achieving a _50% PI reduction at 5 minutes were 12.8% versus 2.1% ( p50.001), and at 10 minutes were 36.9% versus 9.7% ( p50.001), respectively.
• Both treatments were well tolerated. In the safety population (n ¼ 139), 56.8% (n ¼ 79) of patients experienced _1 AE during the trial. The only AE that occurred in _5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n ¼ 19), none were considered to be related to either study medication.
• There was a weak correlation between effective INFS doses and background opioid doses.

Treatment administration:
• Up to four episodes of BTP per day were treated with study medication, intranasal fentanyl spray (INFS), as described below.
• Intranasal fentanyl spray has recently received marketing authorization from the Committee for Medicinal Products for Human Use and will be launched under the trade name Instanyl (Nycomed, Denmark).
• Doses of 50, 100 and 200 mg fentanyl (using INFS solutions of 0.5 mg/ml, 1.0 mg/ml and 2.0 mg/ml, respectively) were taken as a single dose in one nostril. A second INFS dose was permitted 10 minutes after the first, if required, taken in the other nostril. Rescue analgesics were permitted 10 minutes after the second INFS administration if pain relief was still insufficient.
• The comparator medication, oral transmucosal fentanyl citrate (OTFC) (Actiq, Cephalon, USA), was used at six doses: 200, 400, 600, 800, 1200 or 1600 mg in the form of single compressed lozenges with integral oromucosal applicators. One lozenge equalled one dose. OTFC was administered according to manufacturer’s recommendations (15 minutes in the oral cavity between cheek and gum). A second OTFC dose was permitted 30 minutes after the first, if required. Rescue analgesics were allowed, as needed, 45 minutes (if a second OTFC dose was not taken) or 60 minutes (if a second OTFC dose was taken) after start of administration.

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Medication Pearls For Practice: Methadone And Sleep Apnea

"Medication Pearls For Practice" is a new column to be a regular feature here at Onco-PRN. With my role in the Pain and Paliative Care Clinic, expect a lot of pain and symtom control related medication topics. Of course, oncology medications will also be featured.

In this post, key points taken from the Pharmacist's Letter are in bold and italicized.

From: Canadian Pharmacist's Letter 2008; 15(10):241007

Medications that Can Exacerbate Sleep Apnea

“A number of medications, especially CNS depressants such as opioids, benzodiazepines, and muscle relaxants can potentially exacerbate sleep apnea.

*Recently, central sleep apnea has been reported with chronic opioid use and up to 30% of stable methadone maintenance treatment patients have central sleep apnea. In one study (n=50), patients on methadone maintenance therapy were found to have significantly less rapid eye movement (REM) sleep. Central sleep apnea occurred more often in non-REM sleep in methadone maintenance therapy patients. In contrast, respiratory disturbances occur more often during REM sleep with obstructive apnea. These patients had normal resting cardiac function.

*In another study (n=140), the association of methadone, non-methadone opioids, and benzodiazepines with sleep apnea was examined. In the study, patients taking methadone and benzodiazepines concomitantly were found to have a significantly higher rate of central sleep apnea. In the 33% of patients taking methadone, the median daily dosage of morphine equivalents was 187.5 mg/day. The median daily dosage of sustained-release opioids other than methadone in morphine equivalents was 187.5 mg/day. In 36% of patients taking benzodiazepines, the median daily dosage in diazepam equivalents was 15 mg/day. Results of the study showed that 75% of the patients had apnea/hypopnea episodes during sleep. Thirty-nine percent had obstructive sleep apnea, 4% had sleep apnea of an indeterminate type, 24% had central sleep apnea, and 8% had both central and obstructive sleep apnea. Increased dosage of methadone was associated with a higher incidence of central sleep apnea. In contrast, equivalent doses of non-methadone opioids were not found to be associated with increased risk for sleep apnea. The combination of methadone and benzodiazepine also caused significantly more sleep apnea. There are data suggesting that benzodiazepines could possibly inhibit methadone metabolism, prolonging its effect; therefore, this combination should be used cautiously.

In both of these studies presentation of central sleep apnea was atypical compared to those with chronic heart failure (no Cheyne-Stokes respiration, no crescendo-decrescendo pattern of tidal volume).

The cause of central sleep apnea associated with chronic opioid use is likely multifactorial, involving the change of sleep architecture (REM, non-REM, sleep stages, etc) and respiratory depression effect.

Patients with sleep apnea are more likely to experience exacerbation of symptoms when treated with opioids. It is especially important to use caution when titrating opioid analgesic doses in this patient population. The use of patient controlled analgesia (PCA) should be monitored closely in this patient population.”

Feel free to comment below and if you would like to contribute to this featured column topic, "Medication Pearls For Practice", email me at: chrisral@albertahealthservices.ca

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Continuing Education And Certificate Programs

There are some great CEU programs out there. I wanted to highlight just a sampling of these.

Projects In Knowledge have some great individual CEUs, as well as various certificate programs. You can do individual courses or complete them all to obtain the certificate. All are free, but you need to register.

1. The Advanced Certificate Program: Lung Cancer Management
Curriculum I courses present a basic overview of management strategies for optimal personalized care of lung cancer patients. Curriculum II presents more-advanced courses that build on scientific advances and the topics covered in Curriculum I.

2. The Advanced Certificate Program: Breast Cancer Management
Curriculum I courses present a basic overview of management strategies for optimal personalized care of breast cancer patients. Curriculum II presents more advanced courses that build on new scientific developments and the topics covered in Curriculum I.

3. The Certificate Program in Advanced/Metastatic Colorectal Cancer features the very latest information about:
- Colorectal Cancer Diagnosis
- Colorectal Cancer Treatment
- Colorectal Cancer Disease Management

4. The Advanced Certificate Program in Hepatocellular Carcinoma

5. Caring for Oncology Patients: Tips and Tools for Managing Targeted Therapy
"The curriculum offered in this CME/CE program promises to be a timely and continuously updated source of practical information that can be immediately used in treating, monitoring, and managing side effects in cancer patients receiving targeted therapy."


Other CEUs to be had include:
- PainEDU CE Course:
"Interactive case-based learning modules address a range of topics in pain assessment and pain management. Articles and treatment recommendations explore a balanced approach to care with the patients who are prescribed opioids. Update your clinical skills, test your knowledge, and enhance your approach to care!"

- CaPHO's "HOPE" series of CE features topics such as: CINV, Epigenetics, and Molecular Biology of Cancer and Promise of Targeted Therapy.

- Advancing the Safe and Appropriate Use of Oral Chemotherapy Agents: An Interdisciplinary Educational Series for Healthcare Professionals

- http://www.oncologyeducation.ca/ - have to register


Feel free to post other CEUs you find in the comments.

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