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In this issue: March 2017

Dose Changes and Justifications: A Reminder to Prescribers

Documenting the clinical justification for dose increases is an important component of care.

Specific withdrawal symptoms such as hot flashes, muscle or bone ache, irritability, anxiety, sweats or insomnia need to be documented along with the timing of the withdrawal from the last dose. The timing of drug use and identification of the drugs or the route used (e.g. snorting, smoking, etc.) along with the timing of cravings is a necessary part of the clinical justification of dose increases. The rationale for dose increases is supported mainly by the patient’s history. The reason for a dose increase is often multi-factorial with situational stressors often playing a role.

An example of a note that justifies a dose increase is the following:

“Patient injecting one quarter gram heroin every evening. His methadone wears off 15 hours later and he reports hot flashes, bone aches, irritability, sweats and anxiety around this time. His heroin cravings increase during the evening. He denies any sedation or side effects from methadone. He wants a higher blocking dose as he still gets a euphoric effect when he uses.”

The following is an example of a note that does not justify dose increase:

“Patient can't sleep and wakes up achy in the am. He craves heroin and wants increase in dose.”

Challenges in dose increases
Patients who are on carries and who are also abstinent may occasionally request a small dose increase.

Isolated dose increases of 5 to 10 mg may occur and may be justified in view of a wearing-off phenomenon that some patients experience. It is important to determine whether the dose increase is a response to patient stress, real withdrawal symptoms, or cravings. Repeated requests for dose increases greater then a total of 15 mg warrant a reduction in carries. Isolated dose increases may be justified and carries status may remain unchanged.

Patients that are requesting dose increase above 120 mg
Dose increases above 120 mg are rarely indicated.

Patients who are on high range dosing are often unable to gauge what "normal" feels like. There is a paradoxical effect at higher range dosing that may mimic withdrawal but is, in fact, pseudo-withdrawal. High range dosing may cause constipation and fluid retention which can aggravate joint aches and general feelings of malaise. Patients may sleep more often during the day and not sleep at night. This day and night reversal may result in the patient believing that his dose is not lasting at night.

Higher dosing leads to sweats and fatigue with low libido which can also be mistaken for withdrawal. Some patients may be looking for a nodding-off feeling from methadone. Determining whether the dose increase request is side-effect related or the consequence of real withdrawal is important. Ongoing cocaine or alcohol use can lead to feelings of withdrawal that may not reduce substance use at higher doses of methadone. Ongoing opiate use is the best gauge in determining that a dose of greater than 120 mg is indicated.

Dose increases are often requested after a patient misses a day.
A dose increase after one missed day is never indicated.

Dose increases are typically in the 5 to 10 mg range during stabilization. Typically, the dose increase for a previously stable dose is 5 mg. It is rare that a 15 mg dose increase is indicated and the physician needs to ensure that no high risk features are in place such as benzodiazepine use, street methadone or fentanyl use. If the physician is not an experienced methadone prescriber, it is best to dose conservatively.

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Methadone Q&A

Q. I have a patient who is prescribed 80 mg of methadone and has been on the program for more than four years. She has been stable at this dose for approximately one year and she is currently up to six carries. She has not used any substances for the last two years or more. She says that now, her dose is not lasting for the last week. She feels that she needs a dose increase. I know that patients should not develop tolerance to methadone, so, why would a stable patient require a dose increase? Do I need to decrease her carries?

A. This is a common occurrence for patients who have been on a stable dose, but, it is not always due to withdrawal. You are correct in that patients who are prescribed methadone should not develop a tolerance to it. They should not require dose increases once they are stable on a dose. However, there are different circumstances that can interfere with methadone metabolism and different situations where a patient may experience what they interpret as withdrawal symptoms.

When this patient is seen you may want to consider asking the following questions:

  • Have any new medications been prescribed?
  • Has the patient started taking any vitamins or other over-the-counter medications?
  • Has the patient had (or does she have) a viral illness? This may be misinterpreted as having withdrawal symptoms.
  • Have there been any recent stressors in her life? Patients who are feeling more stressed, down, or anxious may also feel physical symptoms that they are interpreting as withdrawal symptoms.

If the patient reports that this issue has just come up then there may be something other than withdrawal causing her to feel symptoms.

What are the specific withdrawal symptoms and when are they occurring. Patients often complain of withdrawal symptoms. However, upon further examination, their symptoms may not be typical of withdrawal symptoms. Two examples might be a patient who complains of feeling tired all day, experiencing no change when they take their dose, but feeling no worse as the day wears on, or, a patient who complains of nausea but no other symptoms of withdrawal.

It is always possible that these symptoms are due to other medical or mental health issues such as pregnancy, viral illness, infection, anemia, depression or anxiety.

Many patients on a stable dose tend to even out and settle down within a week. Immediate encouragement and follow-up within two weeks may help to resolve this situation. Often, symptoms may disappear as quickly as they emerged.

Unless you can establish that this patient is unquestionably experiencing withdrawal, it is worthwhile to consider waiting two weeks before focusing on a dose increase.

If the patient is indeed suffering withdrawal symptoms, they would be of a very typical pattern. This would include the dose wearing off at approximately the same time each day, and, typical withdrawal symptoms including chills, sweating, yawns, sneezing, watery eyes, runny nose, aches, increase anxiety, edgy, antsy, restless etc. that occur at a predictable time following their dose. If the symptoms are a typical cluster of those associated with withdrawal, occurring at the same time each day for more than a week, a small dose increase can help (5mg - 10mg maximum).

There is no need to decrease carries due to the above.

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Testosterone Replacement Therapy

—by Heinz G Mayr, BSc MD

A low testosterone level is reported as a side effect in 80% of males receiving Methadone or Suboxone treatment. This article offers some guidelines for diagnosing and treating low testosterone.

Testosterone Replacement Therapy (TRT) is an essential component of the complete comprehensive care of men on Methadone (Suboxone) Maintenance Treatment (MMT).

Patients presenting symptoms including low energy, low sex drive, loss of muscle mass, osteoporosis or ennui, with a total testosterone level of less than 9 (a normal level is 8.4-29 nmol/L) and/or a free testosterone level of less than 200 (a normal level is 196-636 pmol/L) will benefit dramatically from TRT. Some chronic illnesses, like Hepatitis C, can cause an elevation of sex hormone binding globulin and present an erroneously normal total testosterone level. It is essential to determine both the free and total testosterone levels. Bioavailable testosterone level testing is not covered by the Ontario Health Insurance Plan (OHIP) [as of March 2017], and is not necessary.

The best treatment is depot intramuscular injections, every two weeks, of 200 mg of testosterone as Delatestryl, enanthate, available in 5 ml vial in sesame oil, or, Depotestosterone, cypionate, available in 10 ml vial in cottonseed oil. These five dose vials of testosterone are covered by the Ontario Disability Support Program (ODSP) and cost about $68 for five doses [as of March 2017]. While these preparations are the same drugs as those often used inappropriately by bodybuilders, the 200 mg IM every two weeks dose is a physiological dose and replaces what the body is not producing in MMT males.

Allergic reactions to depot shots are extremely rare as are side effects. Either of these preparations may cause acne in some men. This may be alleviated by switching to the other preparation. There is no conclusive evidence that TRT increases the risk of prostate cancer or cardiac disease.

These patients need the testosterone injections during the full course of MMT to get the positive metabolic effects. Taper the dose as follows: 150 mg of testosterone as the methadone dose is tapered to 15 mg/day; 100 mg of testosterone per 10 mg of methadone; and, 50 mg of testosterone per 5 mg of methadone. Only 15% of men are able to taper off MMT.

The pre-treatment workup includes a focused physical exam to rule out other illness such as breast or testicular cancer, congestive heart failure, liver failure, prostate cancer, and polycythemia with hematocrit greater than 55. Blood work would rule out prostate cancer with the PSA in men over 40 years of age. Other tests are:

  • TSH, Hep C, HIV, CBC, and LFT to rule out other causes of fatigue.
  • Serum ferritin level to rule out hemochromatosis.
  • FSH, LH, Prolactin to rule out primary hypogonadism.

Most men in the MMT program will have secondary hypogonadism with low to normal FSH, LH, and Prolactin as a result of the effect of opiates on the hypothalamic-pituitary-testicular axis with resulting low testosterone and low sperm count. Blood work should be repeated yearly and their PSA level must be monitored to watch for prostate cancer. A PSA level greater than 4 ngm/ml, or an increase in the velocity of greater than 1.4 ngm/ml per year requires a urological referral. Most of these men refuse the rectal exam, especially if informed that it is not that reliable in detecting prostate cancer.

Many men on MMT, but not on TRT, continue to use stimulants (uppers) such as Ritalin, Cocaine, or Methamphetamine to treat symptoms of low testosterone. They would benefit more from TRT. It is essential to screen each and every one of your male MMT patients.

After about three months of regular depot IM shots every two weeks, repeating the blood test for testosterone level 7 days after the last shot should give a level of about 25 for total testosterone and 500 for free testosterone. Some men need to have the dosage increased to 250 mg every two weeks if levels are not in the therapeutic range. A Haematocrit greater than 55 would necessitate a dose decrease.

Blood tests on these men can be done any time of day rather than insisting on a morning sample. This can result in better compliance in this challenging population.

Testosterone vials should not be released by the pharmacy directly to the patient due to the high likelihood of diversion. The vials should be directly delivered to the physician’s office. They can be stored alphabetically in egg cartons on a shelf in a locked room for safety. They do not need to be refrigerated. The manufacturer states that the multi-dose vials have an expiry date of at least two years and can be used repeatedly unless they go cloudy.

Testosterone gels and tablets are prone to misuse. Depot IM injections in physician’s office avoid that risk.

If you are, or plan to be, the TRT physician in your area then it is best to have flexible TRT clinic hours, including one evening a week and Saturday mornings, as many of these men return to work as a result of the therapy. It is helpful to hand out a photocopied calendar sheet with the patient’s next appointment clearly indicated to remind them as every two week appointments may be hard to remember for some. It is possible to administer TRT as part of the regular methadone visit and bill G372 [as of March 2017]. It is also possible to setup a separate TRT-only clinic and have patients see a methadone physician and a testosterone physician on the same day, with separate billing.

We use sterile, single-use, 20 gauge, 25 mm needles with Luer lock and usually do the depot injection into the buttock, drawing back before injection to make sure we are not injecting into a vein. We have the patient rub the site for 20 seconds once we withdraw the needle to prevent bleeding or leakage. Infections or hematomas with this method are extremely rare.

The half-life of Delatestryl is 8 ½ days, and Depotestosterone is about 7 days. Some men notice they are symptomatic by Day 10-14. Some men prefer to get a half dose (100 mg) every week when they are in for their methadone visit, as it gives better symptomatic control.

Infertility with low sperm counts may occur due to MMT or opiate usage. This is due to low FSH resulting in low Sertoli cell functioning and low spermatogenesis. These testosterone shots do not improve low sperm count. TRT is just replacing the testosterone that is not made by the patient due to decreased LH stimulation of Leydig cells. Infertility and normal testosterone production may improve if the patient eventually gets off the MMT program and opiates.

It can take about three months, or six or seven shots, to get the full metabolic changes resulting in muscle weight gain of 15 pounds, fat loss, increased sex-drive, and improved mood and ambition.

Informative scientific articles that you can access online and read to get an in-depth summary of this issue are:

  • Hassan J, Barkin J. Testosterone deficiency syndrome: benefits, risks, and realities associated with testosterone replacement therapy. The Canadian Journal of Urology. 2016; 23 (11): 20-30.
  • Morales A, Bebb R, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Canadian Medical Association Journal. 2015; 187 (18): 1369-1377.

About the author: Heinz Mayr, BSc, MD earned his BSc. from the McGill University (1970) and his medical degree at the University of Western Ontario (1975). He lives in London, Ontario and maintained a general practice there from 1975 to 2007. He has practiced in the area of MMT and TRT since 2007. His article outlines a protocol developed by Dr. Mayr in over five years of treating these men at Clinic 528 in London, Ontario and reviewing the relevant literature.

Colleagues can contact Dr. Mayr with any questions and may arrange to audit one of his Saturday morning clinics (please contact him for details).

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Diane Doherty, Chair

Word from the Chair

The members of the Methadone Committee would like to announce that Ms Diane Doherty, Chair of the Methadone Committee, has resigned from Council. Ms Doherty has been on the Methadone Committee as a Public Member of Council for a number of years and served as Chair of the Committee for the past two years. The Committee appreciated the input of Ms Doherty and wish her well in her future endeavors. At the time of the posting of this newsletter the Committee is waiting to hear from Governance on who the new Committee Chair will be. We anticipate introducing the new Chair in the next newsletter.

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