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A Phase I Study to Determine the Dose of Methadone as a First Line Agent in the Treatment of Chronic Neuropathic Cancer Pain

Phase 1
18 Years
Not Enrolling
Nausea and Vomiting, Pain, Sleep Disorders, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study to Determine the Dose of Methadone as a First Line Agent in the Treatment of Chronic Neuropathic Cancer Pain



- To determine the optimum starting dose (defined as the dose that does not require
modification within the first 4 days of treatment for lack of efficacy or the
occurrence of adverse events) of methadone hydrochloride as a first-line opioid
treatment in patients with chronic neuropathic cancer pain.


- To assess the number and timing of breakthrough analgesic usage.

- To assess the number of episodes of breakthrough pain.

- To assess the total daily dose of methadone hydrochloride.

- To assess the average pain score.

- To determine the safety and adverse event profile of methadone hydrochloride as a
first-line opioid in the treatment of chronic neuropathic cancer pain.

- To assess the frequency and severity of sleep disturbance associated with the use of
methadone hydrochloride.

- To determine the feasibility of recruiting patients with chronic neuropathic cancer
pain in a reasonable time frame for a future phase III study of methadone hydrochloride
vs morphine.

OUTLINE: This is a multicenter study. Patients are assigned to a group according to their
average daily dosage of morphine-equivalent for the 3 full days prior to study entry (≤ 45
mg/day OR > 45 but ≤ 75 mg/day).

Patients receive oral methadone hydrochloride at various doses every 8 hours. Patients also
may receive breakthrough oral methadone hydrochloride every 2 hours, as needed, for up to 6
breakthrough analgesics per day. Treatment continues for up to 35 days. Treatment stops if
the patient has well-controlled pain or experiences intolerable side effects.

Patients complete the Short-Form McGill Pain Questionnaire at baseline. Patients rate their
pain according to questions from the Brief Pain Inventory on a scale of 0 (no pain) to 10
(worst pain imaginable) to best describe pain at its worst in the last 24 hours, pain at its
least in the last 24 hours, pain on average, and pain right now; record the number and
timing of breakthrough analgesic usage, the number of episodes of breakthrough pain, and the
total daily dose of methadone hydrochloride; and complete nausea and sleep assessments once
daily on days 1-14.

After completion of study treatment, patients are followed at 4, 6-7, and 28 days.

Inclusion Criteria


- Patients diagnosed with cancer and experiencing chronic neuropathic pain syndrome

- Pain syndrome diagnosed by the investigator

- Pain syndrome related to the effects of cancer or its treatment (i.e.,
chemotherapy, radiotherapy, and surgery)

- Meets 1 of the following criteria:

- Need to be started on strong opioids

- Require an increase in opioid dose and are currently taking ≤ 75 mg of
total daily dose of oral morphine equivalent

- Experiencing pain for ≥ 4 weeks with an average pain score of ≥ 4 or a worst pain
score of ≥ 5 (using the 0-10 Brief Pain Inventory Scale) during the past 24 hours

- Requires strong opioids to control pain and is using an oral morphine-equivalent dose
of 0-75 mg per day, on average, including breakthrough analgesia, within the past 3
full calendar days

- Mixed pain syndrome allowed provided the neuropathic component is the predominant

- Meets 1 of the following criteria:

- Receiving concurrent chemotherapy but the chronic neuropathic pain is not
related to this treatment and is not expected to improve or worsen because of
this therapy

- Received prior chemotherapy but discontinued treatment, has not received
chemotherapy within the past 7 days, and no further chemotherapy is planned

- No prior chemotherapy


- Karnofsky performance status 40-100%

- ALT and AST ≤ 3 times upper limit of normal (ULN)

- Creatinine ≤ 2 times ULN

- No other known laboratory abnormality that, in the investigator's opinion, would
contraindicate study participation

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Mini-Mental State Examination score ≥ 25/30

- Able to speak, read, and write in either English or French

- Willing to complete study diary and questionnaires

- Available for study treatment and follow up (i.e., within reasonable geographical
limits of the participating center)

- Able to swallow and tolerate oral medications

- Patients with prior exposure to methadone hydrochloride must be able to tolerate it

- No intractable nausea and vomiting

- No presence or history of unstable disease or condition that would, in the
investigator's opinion, preclude patient participation in study treatment, such as:

- Head injury

- Increased intracranial pressure

- Uncontrolled seizures

- Uncontrolled asthma

- Decompensated chronic obstructive pulmonary disease

- Untreated prostate hypertrophy

- Acute abdominal conditions

- Untreated hyperthyroidism and Addison disease

- Increased cerebrospinal fluid pressure

- Urethral stricture

- Severe cardiac arrhythmias (especially prolonged QT interval)

- Symptomatic hypotension

- Toxic psychosis

- Cor pulmonale

- Sleep apnea

- Severe obesity

- Kyphoscoliosis

- Myxedema

- Central nervous system depression

- Coma

- No history of significant alcohol, analgesic, or narcotic substance abuse within the
past 6 months

- Able physically and mentally to answer questions and comply with study treatment

- No patient who lives alone and cannot access at least 1 caregiver who can monitor on
a daily basis at home


- See Disease Characteristics

- More than 3 weeks since prior radiopharmaceutical treatment or radiotherapy

- Concurrent co-analgesics and medications that can affect methadone hydrochloride
metabolism allowed provided patients have been on a stable dose for the past 3-5 days
and ≥ 5 half lives have passed since any change in dose

- Not scheduled to start chemotherapy during the study treatment

- Not planning on starting or discontinuing medication associated with modified
methadone hydrochloride clearance during study treatment

- No concurrent therapeutic procedure that is likely to influence pain intensity during
the study period

- No concurrent other opioid medications

- No other concurrent methadone hydrochloride

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

Optimum starting dose

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Bruno Gagnon, MD, MSC

Investigator Role:

Study Chair

Investigator Affiliation:

McGill Cancer Centre at McGill University


Canada: Ethics Review Committee

Study ID:




Start Date:

April 2009

Completion Date:

September 2011

Related Keywords:

  • Nausea and Vomiting
  • Pain
  • Sleep Disorders
  • Unspecified Adult Solid Tumor, Protocol Specific
  • sleep disorders
  • nausea and vomiting
  • unspecified adult solid tumor, protocol specific
  • pain
  • Nausea
  • Vomiting
  • Sleep Disorders
  • Parasomnias