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David E Joranson, MSSW Editor's note: The following article is a contributed commentary. I would like to thank Dr. Forest Tennant for his permission to refer to and quote from his work, The Dilemma of Severe Incurable, Narcotic-Dependent Pain Patients Referred to Narcotic Treatment Programs: Need for Administrative, Regulatory, and Legislative Relief (1996).

According to Dr. Forest Tennant, a California physician who operates a number of methadone maintenance treatment programs in Califomia, chronic pain patients are gaining admittance to methadone maintenance programs not because they are addicts, but only for pain management. The apparent reason is that these patients lack either access to other programs or physicians who are willing to use opioid analgesics, especially in high doses.

Methadone programs (officially known as narcotic treatment programs [NTPs]) are specially registered with the federal and state govemments as the only lawful means of using opioids for the maintenance treatment of opioid dependence, or addiction. However, opioid analgesics, including methadone, may be prescribed for patients with pain, including intractable pain, by any physician who can prescribe controlled substances.

Dr. Tennant says his programs are treating approximately 200 chronic pain patients, not for addiction, but for pain. Tennant explains that these admissions are necessary due to a "lack of understanding, disbelief, or bias" among Califomia physicians about the high dose opioid therapy that some patients with severe chronic pain need (Tennant, 1996).

Writing to expose the situation and to stimulate discussion and response, Dr. Tennant says that despite the 1990 Califomia Intractable Pain Treatment Act (IPTA) (California Business and Professions Code, 1980), there has been an in-crease in the number of patients with severe intractable pain who are referred to his NTPs. Although the Califomia IPTA endorsed opioid treatment for in-tractable pain, Dr. Tennant asserts there remains a strong reluctance among physicians to prescribe the quantities of opioids needed by patients with severe chronic pain.

Regulatory authorities in California have been among the most proactive in the country in reducing practitioners' fears about regulatory scrutiny and improving knowledge about pain management (Board of Registered Nursing, 1994; Califomia Medical Board, 1995a, 1994b; California State Board of Pharmacy, 1996; Joranson, 1994).

Dr. Tennant contends that these patients are very ill, disabled, and have limited funds. Further, he states that he "has not been able to identify one solitary referral or placement site for the incurable, narcotic dependent pain patients referred to us. We are viewed as the 'last resort' treatment facility" (Tennant, 1996, p.5).

Several questions are obvious. First, is it permissible under federal regulations for pain patients to be admitted to NTPs? It appears so. Federal regulations state that methadone may be used to treat a "narcotic dependent" person, defined as "an individual who physiologically needs heroin or a morphine-like drug to prevent the onset of withdrawal" (Narcotic Addict Treatment Act, 1974). Most pain patients who take opioids regularly for chronic pain would meet this outdated and incorrect definition of opioid dependence.

In 1995, an Institute of Medicine (IOM) Committee of the National Academy of Sciences issued a report on the federal regulation of methadone treatment, which recognized in part that physicians who are uneasy about chronic opioid therapy may make inappropriate referrals to methadone programs (Institute of Medicine, 1995).

After studying the situation, the IOM committee said that treatment of pain and treatment of opioid addiction should, as a matter of policy, remain distinct, and made the following recommendation: "...the IOM committee proposes that the [federal] regulations establish a clear distinction between opiate addiction and dependence and that any guidelines developed for methadone treatment incorporate this distinction" (Institute of Medicine, 1995, p. 211).

Unfortunately, the IOM committee's use of terms only adds to the confusion, since the term dependence is roughly synonymous with addiction (Joranson, 1995). It would have clarified matters if the committee had simply said that the federal regulations should establish a clear distinction between the treatment of opioid dependence and the treatment of pain. This may well have been the intent of the committee, which went on to recommend "...that the [federal] regulations prohibit the admission of a person being treated solely for chronic pain to an opiate addiction treatment program for treatment as an opiate addict" (Institute of Medicine, 1995, p. 211).

The IOM proposal to prohibit, by federal regulation, the future admission of chronic pain patients to addiction treatment programs seems to be a reasonable policy approach to differentiate the treatment of addiction from the treatment of chronic pain. The policy would reserve needed treatment slots for addicts while endorsing the treatment of chronic pain patients in the general healthcare system.

Second, how many chronic pain patients are in methadone programs, and what are the reasons?  Have these patients received all that the pain management system has to offer them?  Based on my personal communications with state agencies, methadone programs, and law enforcement personnel, it appears that the admission of chronic pain patients to methadone programs is real and is probably not limited to California.  A survey of methadone maintenance programs in the United States could be accomplished quickly with the help of the National Institute on Drug Abuse. If it demon-strates a national pattern, there are ethical and policy issues as well as practical ques-tions about patients' access to pain management services that must be addressed.

Third, is legislation the answer to improving patients' access to pain management?   There is already a marked trend in the United States to address underprescribing of opioids for pain through state legislation, including IPTAs. However, some of the IPTAs pose new requirements and restrictions on the treatment of chronic pain (Joranson & Gilson, 1997), and potentially conflict with the consensus statement that the American Academy of Pain Medicine (AAPM) and APS recently adopted entitled The Use of Opioids for the Treatment of Chronic Pain (1996).

In part, this trend in new state laws on pain is the result of the advocacy activities of well- intended chronic pain patients who have met with frustration in their attempts to obtain access to adequate pain relief, including opioids. Proposals for more pain legislation are being discussed in many states, including Califomia. We should ask how adopting more laws will improve patients' access to appropriate pain management.

Isn't the immediate need to directly assist chronic pain patients in locating professionals and programs that will provide high quality treatment, including opioids? Aren't many patients receiving chronic opioid therapy from physicians and pain management programs all over the country?

One way to address this need for better patient access would be for professional organizations such as APS to experiment with sponsoring informal meetings between pain programs and patient groups, not at the national level, but at the community and state levels. Pain program directors could explore ways to make pain management more accessible to people in their own vicinities. Patients who have "failed" to obtain relief from what the system has provided so far merit particular attention. We should accept that some of these patients and families may feel frustration and anger.

The pain field is evolving under all sorts of influences. Professionals in an evolving field should pay close attention to policy developments, including what happens on the periphery of the field, because this is where policy issues sometimes germinate. In that sense, we should take note of two ironies on the periphery of the pain field that are full of policy ramifications: that methadone mainten-ance programs for drug addicts may, in some locations, offer a last resort for chronic pain patients and that chronic pain patients are helping to get laws passed that may result in more, not less, regulation of pain management. The policy issues here are not simple; however, there is one clear line of direct action that addresses the underlying issue in both: We need to become much more active in improving patients' access to effective pain management.

David E. Joranson is director of the Pain and Policy Studies Group, University of Wisconsin Comprehensive Cancer Center and the World Health Organization Collaborating Center for Policy and Communications in Cancer Care.

References


American Academy of Pain Medicine and American Pain Society.). The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Glenview, IL: Author.

California Board of Registered Nursing. (1994). Pain management policy. Summit on effective pain management: Removing impediments to appropriate prescribing, 42.

Cal. Bus. & Prof. Code Chapter 1588 §2241.5(b) (1990).

Califomia Medical Board. (1994a, October). Text of "Guideline for prescribing controlled substances for intractable pain." Medical Board of California Action Report, 1, 8.

California Medical Board. (1994b). A statement by the medical board: Prescribing controlled substances for pain. Federation Bulletin: The Journal of Medical Licensure and Discipline. 81(3),203-205.

California State Board of Pharmacy. (1996). Dispensing controlled substances for pain: A statement of the Califomia State Board of Pharmacy. Health Notes, 4-5.

Institute of Medicine. (1995). Federal regulation of methadone treatment. Washington, DC: National Academy Press.

Joranson, D.E. (1994). California sponsors pain summit; Maryland fends off new regulations. APS Bulletin, 4(3), 11-12.

Joranson, D.E. (1995). Current thoughts on opioid analgesics and addiction. Symptom Control in Cancer Patients, 6(1), 105-110.

Joranson, D.E., & Gilson, A.M. (1997). State intractable pain policy: Current status. APS Bulletin, 7(2),7-9.

Narcotic Addict Treatment Act. Code of Federal Regulations, 21 §291.505 (a)(5) (1974).

Tennant, F. (1996). The dilemma of severe incurable, narcotic-dependent pain patients referred to narcotic treatment programs: Need for administrative, regulatory, and legislative relief. West Covina, CA: Research Center for Dependency Disorders and Chronic Pain Community Health Projects Medical Group.



Methadone is an effective opioid analgesic for severe pain. Because of low cost (a month's supply may be US$ 5-10) and apparent efficacy in complex pain syndromes, it is increasingly used as a first-line opioid. It is, in effect, a combination drug - part opioid and part NMDA receptor antagonist.   Methods of dose conversion to methadone from other opioid analgesics that account for this dual action were discussed in Fast Fact : Methadone for Pain.  This Fast Fact will describe strategies for beginning methadone when the patient has not been taking a strong opioid.  Note: due to its complex pharmacology, physicians unfamiliar with methadone are advised to seek consultation prior to initiating therapy.

Methadone is lipophilic, thus it takes time to develop tissue stores that maintain serum levels. Note: There is enormous interindividual variation.
After a single dose there is a short distribution phase (associated with acute pain relief) with half-life of 2-3 hours and a slow elimination phase (half-life 15-60 hours).

Dosing must account for the accumulation of drug over days. It is this accumu-lation that accounts for most therapeutic misadventures. Liver metabolites are inactive; therefore no dose reduction is required with renal failure. After steady-state is reached, about two-thirds of patients will get adequate pain relief maintained with twice a day (bid) dosing. Note: a number of drugs will alter methadone metabolism, there needs to be close follow-up and attention to the addition or subtraction of interacting medications

There are several approaches to starting methadone for the treatment of pain. All take into account the long-half life of the drug that leads to drug accumulation over days. The following discussion presents approaches based on the literature and the authors clinical experiences.

Conservative Approach

1. Begin fixed dose methadone 5 or 10 mg orally bid or tid for 4-7 days.

2. If incomplete pain relief, increase the dose by 50% and continue for 4-7 days.

3. Continue increasing dose every 4-7 days until stable pain relief achieved.

4. Breakthrough pain: use an alternative short acting oral opioid with short half-life (e.g. morphine 10 mg) every 1 h prn for breakthrough pain and to provide pain relief during titration phase.

Loading Dose Approach

1. Load: Start methadone at fixed oral dose (e.g. 5 or 10 mg) q 4h prn only.

2. Calculate Maintenance: On day 8, calculate the total methadone dosage taken over last 24 h period and give in divided doses bid or tid. Give 10% of total daily methadone as prn drug q1h for breakthrough pain. Instruct the patient to call you if they need to use more than 5 breakthrough doses per day.

Conversion to Methadone From Another Strong Opioid

Calculate Total Methadone Dose (fsee conversion chart below). Convert step wise in order to detect if the patient demonstrates a therapeutic response to a much lower dose of methadone that you had expected.

Day 1: Replace 1/3 of opioid dose with oral methadone on bid or tid schedule

Day 2: Replace next 1/3 of opioid dose.

Day 3: Complete change to methadone.

ReferenceBruera E, Sweeney. Methadone use in cancer patients with pain: a review. J Pall Med 2002; 5:127-138.

Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Citation for referencing. Fast Facts and Concepts #86 . Methadone: Starting dose information. Von Gunten, CF., March 2003. End-of-Life Physician Education Resource Center www.eperc.mcw.edu.



Methadone, a potent opioid agonist, has many characteristics that make it useful for the treatment of pain when continuous opioid analgesia is indicated.  Although available for decades, its use has gained renewed interest due to its low cost and potential activity in neuropathic pain syndromes. Unlike morphine, methadone is a racemic mix; one stereoisomer acts as a NMDA receptor antagonist, the other is a mu-agonist opioid. The NMDA mechanism plays an important role in the prevention of opioid tolerance, potentiation of opioid effects, and efficacy for neuropathic pain syndromes, although this latter impression is largely anecdotal.

Any clinician with a Schedule II DEA license can prescribe methadone for pain; a special license is only required to prescribe methadone for the treatment of addiction. In some jurisdictions, it is necessary to apply the words "for pain" on the prescription.

Methadone is highly lipophilic with rapid GI absorption and onset of action. It has a large initial volume of distribution with slow tissue release. Oral bioavailability is high, ~ 80%. Unlike morphine there are no active metabolites; biotransformation to an active drug is not required. The major route of metabolism is hepatic with significant fecal excretion; renal excretion can be enhanced by urine acidification (pH <6.0). Unlike morphine, no dose adjustment is needed in patients with renal failure since there are no active metabolites. Methadone is available in tablet, liquid and injectable forms; oral preparations can be used rectally. Parenteral routes include IV bolus dosing or continuous infusion.

Unlike morphine, hydromorphone or oxycodone, 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. Rapid titration guidelines for other opioids do not apply to methadone.

Given recent reports that high-dose methodone MAY be associated with development of Torsades, depending upon life expectancy and goals of care, EKG monitoring may be appropriate when changes in dosage are made. An important property of methadone is that its apparent potency, compared to other opioids, varies with the patient's current exposure to other opioids.

The chart below indicates the
Daily Oral Morphine Dose Equivalents
followed by the

Conversion Ratio of Oral Morphine to Oral Methadone<100 mg - 3:1 (i.e., 3 mg morphine:1 mg methadone)

101-300 mg - 5:1
301-600 mg - 10:1
601-800 mg - 12:1
801-1000 mg - 15:1
>1001 mg - 20:1

Due to incomplete cross-tolerance, it is recommended that the initial dose is 50-75% of the equianalgesic dose.

Summary

Compared to morphine, methadone is inexpensive, may provide improved analgesia in neuropathic pain and will provide a longer duration of action. Dosing intervals at the start of treatment are q 4-6 hours, and may be increased over time to q 6-12 hours.

Methadone is not indicated in poorly controlled pain where rapid dose adjustments are needed; do not increase oral methadone more frequently than every 4 days.

Dose conversion to:from other opioids and methadone is complex; consultation with pain management specialists familiar with methadone use is recommended.

Patient and family education is essential as they may misinterpret prescription of methadone to mean that their physician believes that they already are an addict.

Copyright and Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Citation for referencing. Fast Facts and Concepts #75 Methadone for the treatment of pain. G Gazelle and PG Fine. September 2002. End-of-Life Physician Education Resource Center www.eperc.mcw.edu

Fast Facts and Concepts was originally developed as an end-of-life teaching tool by Eric Warm, MD, U. Cincinnati, Department of Medicine. See: Warm, E. Improving EOL care--internal medicine curriculum project. J Pall Med 1999; 2: 339-340.

Disclaimer: Fast Facts provide educational information, this information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used. 



:
The need to change from one opioid to another, or from one route to another, is common. The published conversion tables provide a rough guide for making calculations . However, clinical judgement must always be used to arrive at a reasonable dose conversion. The following examples assume a change in drug or route at a time of stable pain control using equianalgesic doses.

Opioid Equianalgesic Values for use with the following examples**

Morphine 10 mg parenteral = Morphine 30 mg oral = Hydromorphone 1.5 mg parenteral = Hydromorphone 7.5 mg oral.

Change route, keeping drug the same (e.g. oral to IV morphine)
Example: Change 90 mg q12 MS Contin to MS by IV continuous infusion

Calculate the 24 hour current dose: 90mg q 12 = 180 mg MS/24 hours

Look up equianalgesic ratio: 30 mg po MS = 10 mg IV MS

Calculate new dose using ratios: 180/30 x 10 = 60 mg IV MS/24 hours or 2.5 mg/hour infusion

Change drug, keep the same route: (e.g. po morphine to po hydromorphone)

There is incomplete cross-tolerance between all different opioids, but the exact amount will differ, thus, equianalgesic tables are only approximations. Depending on age and prior side effects, most experts recommend starting a new opioid at 50% of the calculated equianalgesic dose.

Example: Change 90 mg q 12 MS Contin to oral hydromorphone.

1. Calculate the 24 hour current dose: 90 Q12 x 2 = 180 mg po MS/24 hrs
2. Look up equianalgesic ratio: 30 mg po morphine = 7.5 mg po hydromorphone
3. Calculate new dose using ratios: 180/30 X 7.5 = 45 mg oral hydromorphone/24 hours.
4. Reduce dose 50% for cross-tolerance: 45 x.5 = 22 mg/24 hours = 4 mg q4h

Changing drug and route (e.g. oral morphine to IV hydromorphone)

Example: Change from 90 mg q12 MS Contin to IV hydromorphone as a continuous infusion.

1. Calculate the 24 hour current dose: 90 Q12 x 2 = 180 mg po MS/24 hrs
2. Look up equianalgesic ratio of po to IV morphine: 30 mg po MS = 10 mg IV MS
3. Calculate new dose using ratios: 180/30 x 10 = 60 mg IV MS/24 hours
4. Look up equianal. ratio of IV morphine to IV hydromorphone: 10 mg MS = 1.5 mg hydromorphone
5. Calculate new dose using ratios: 60/10 x 1.5 = 9 mg IV hydromorphone/24 hours
6. Reduce dose 50% for cross-tolerance: 9 x.5 = 4.5 mg/24 hours = 0.2 mg IV continuous infusion

References: Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Publication No. 94-0592. Rockville, MD. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, 1994. (page 54)

Gordon DB, Stevenson KK, Griffie, J, et al. Opioid equianalgesic calculations. J Pall Med 1999;2:209-218

Copyright Notice: Users are free to download and distribute Fast Facts for educational purposes only.

Contact:
David E. Weissman, MD, FACP
Editor, Journal of Palliative Medicine
Palliative Care Program Director
Medical College of Wisconsin
(P) 414-805-4607
(F) 414-805-4608

Disclaimer: Fast Facts provide educational information, this information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

As long as there is still breath in your body;
there is hope you will find the medication to
ease your pain and improve the quality of 
your life. Life is much too precious to live 
each day in agonizing pain.  .

It matters if you just don't give up....

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Updated:  July 3, 2005 

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