Methadone Hydrochloride as First-Line Therapy in Treating Patients With Chronic Neuropathic Cancer Pain

Condition(s) targeted: Nausea and Vomiting; Pain; Sleep Disorders; Unspecified Adult Solid Tumor, Protocol Specific

Intervention: methadone hydrochloride (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: NCIC Clinical Trials Group

Official(s) and/or principal investigator(s):
Bruno Gagnon, MD, MSC, Principal Investigator, Affiliation: McGill Cancer Centre at McGill University

RATIONALE: Methadone hydrochloride may reduce chronic neuropathic pain in patients with cancer.

PURPOSE: This phase I trial is studying the side effects and best dose of methadone hydrochloride as first-line therapy in treating patients with chronic neuropathic cancer pain.

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

Study design: Supportive Care, Non-Randomized, Open Label

Primary outcome: Optimum starting dose

Secondary outcome:

Pain control as assessed by the number and timing of breakthrough analgesics, the number of episodes of breakthrough pain, the total daily dose of methadone, and the average pain scores

Adverse events (including respiratory depression) according to NCI CTCAE v3.0 criteria

Frequency and severity of sleep disturbance from pain

Feasibility of recruiting patients

Detailed description: OBJECTIVES:

Primary

- 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.

Secondary

- 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.

- Group 1 (patients currently receiving morphine-equivalent ≤ 45 mg/day): Patients

receive oral methadone hydrochloride every 8 hours. Patients also may receive breakthrough oral methadone hydrochloride every 2 hours, as needed, for ≤ 6 breakthrough analgesics per day. Treatment continues for 35 days in the absence of well-controlled pain or intolerable side effects.

- Group 2 (patients currently receiving morphine-equivalent > 45 and ≤ 75 mg/day):

Patients receive methadone hydrochloride at a higher dose than in group 1 and breakthrough methadone hydrochloride as in group 1.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Patients diagnosed with cancer and experiencing a 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

pain

- 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

PATIENT CHARACTERISTICS:

- 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

- No physical or mental inability 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

PRIOR CONCURRENT THERAPY:

- 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 opioid medications

- No other concurrent methadone hydrochloride

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: April 2009
Last updated: June 27, 2009