McMaster University

Michael G. DeGroote
National Pain Centre

Scope of Search

Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain

Cluster 2: Conducting an Opioid Trial

R09. Recommendation Statement

No. Recommendation Keyword
R09 When conducting a trial of opioid therapy, start with a low dosage, increase dosage gradually and monitor opioid effectiveness until optimal dose is attained (Grade C). Optimal dose
  • R09. Discussion
  • R09. Summary of Peer-Reviewed Evidence

R09. Discussion

1. Optimal Dose

1.1 Dose: Initial and Incremental

The object of the trial is to determine the optimal dose, i.e., a dose that will improve function or reduce pain intensity by at least 30% without causing major adverse effects or complications. It is recommended to start the opioid trial with a low dose and increase the dose in small quantities. Opioids produce a graded analgesic response: the patient experiences the greatest benefits at lower doses and a plateauing of analgesic response at higher doses. Therefore, slow titration 1) avoids unnecessarily high doses, and 2) reduces the risk of sedation and overdose as it ensures that a dose increase does not exceed the patient’s tolerance. (Consider a three-day “tolerance check” for elderly and other high-risk patients: the nurse, physician, or pharmacist calls the patient/family three days after starting the prescription to check for any signs of sedation.)

See Table B-9.1 for opioid suggested initial dose and titration.

1.2 Attaining Optimal Dose

The optimal dose is reached with a balance of three factors:

  • Effectiveness : improved function or at least 30% reduction in pain intensity
  • Plateauing: effectiveness plateaus — increasing the dose yields negligible benefit
  • Adverse effects/complications: adverse effects or complications are manageable.
1.3 Watchful Dose

Watchful Dose = morphine or equivalent dose exceeding 200 mg/day

See Recommendation 10 for guidance on a watchful dose.

2. Measuring Opioid Effectiveness

Opioid effectiveness = improved function or at least 30% reduction in pain intensity

During an opioid trial, schedule patient visits frequently (e.g., 2–4 weeks) to assess for changes in pain intensity and function.

2.1 Assessing Function Change

The patient’s progress in reaching agreed-on goals is an important indicator of function change. Self-report can be prompted by asking about work, household activity, mood, walking ability, sleep, and social activities. For an example of a structured assessment tool frequently used in trials, see Appendix B-9: Brief Pain Inventory.

2.2 Assessing Pain Change

A 30% or greater reduction in pain intensity is considered clinically significant (Farrar 2001).

Change in pain intensity can be assessed using an 11-point (0–10) numeric rating scale (NRS). With each dose increase, the patient should be asked to estimate the pain intensity: a desirable response is a reduction in pain intensity (e.g., from 9/10 [baseline] to 6/10 [endpoint]) and a longer duration of analgesia per dose.

Example of assessing change in pain intensity:

1. Determine the raw change in the NRS score:
baseline – endpoint, e.g., 9 – 6 = 3
2. Determine the percent change:
raw change x 100, e.g., 3 x 100 = 33%
baseline 9

3. Monitoring for Adverse Effects, Medical Complications, Compliance, and Risks

3.1 Adverse Effects and Medical Complications

See Recommendation 5 for potential adverse effects, medical complications, and risks.

3.2 Compliance

Compliance is indicated when the patient takes the opioids as prescribed and shows no signs of misuse or aberrant drug-related behaviours.

4. Ending Titration

Titration ends when

  • The optimal dose is attained, or
  • Trial is considered a "failed trial."

The following circumstances could indicate a failed trial:

  • The patient experiences insufficient analgesia after two or three dose increases and/or unacceptable adverse effects and/or medical complications (see Recommendation 13).
  • There are indications of misuse or addiction (see Recommendation 12).

5. Documenting the Trial

It is important to record all aspects of the opioid trial in the patient’s chart. Details regarding dose, frequency, opioid effectiveness, adverse effects, medical complications, goal attainment, and compliance are crucial in evaluating the opioid trial outcome.

For documentation templates, see Appendix B-7.

R09 Summary of Peer-Reviewed Evidence

1. Clinically important change for numerical pain scale (NRS)

"On average, a reduction of approximately two points or a reduction of approximately 30% in the PI-NRS represented a clinically important difference. The relationship between percent change and the PGIC was also consistent regardless of baseline pain, while higher baseline scores required larger raw changes to represent a clinically important difference" (Farrar 2001).

Table B-9.1 Opioid Suggested Initial Dose and Titration

Modified from Weaver 2007 with information from the e-CPS (Canadian Pharmacists Association, 2008)

Note: The table is based on oral dosing for chronic non-cancer pain. Brand names are shown if there are some distinct features about specific formulations.

Reference to brand names as examples does not imply endorsement of any of these products.

ASA: acetylsalicylic acid,  CR = controlled release,  IR = immediate release,  NA = not applicable


Initial dose

Minimum time interval for increase

Suggested dose increase

Minimum daily dose before converting IR to CR

Codeine (alone or in combination with acetaminophen or ASA) 15-30 mg q.4 h. as required 7 days

15-30 mg/day up to maximum of

600 mg/day (acetaminophen dose should not exceed 3.2 grams/day)

100 mg daily
CR Codeine 50 mg q.12 h. 2 days 50 mg/day up to maximum of 300 mg q.12 h. NA
Tramadol (37.5 mg) + acetaminophen (325 mg) 1 tablet q.4-6 h. as needed up to 4/day 7 days 1-2 tab q. 4-6 h. as needed up to maximum 8 tablets/day 3 tablets
CR Tramadol

a) Zytram XL®: 150 mg q. 24 h.

b) Tridural™: 100 mg q. 24 h.

c) Ralivia™: 100 mg q. 24 h.

a) 7 days

b) 2 days

c) 5 days

Maximum doses:

a) 400 mg/day

b) 300 mg/day

c) 300 mg/day

IR Morphine
  • 5-10 mg q. 4 h. as needed
  • maximum 40 mg/day
7 days 5-10 mg/day 20-30 mg
CR Morphine
  • 10-30 mg q.12 h.
  • Kadian®: q. 24 h.
    Kadian® should not be started in opioid-naïve patients
Minimum 2 days, recommended: 14 days 5-10 mg/day NA
IR Oxycodone
  • 5-10 mg q. 6 h. as needed
  • maximum 30 mg/day
7 days 5 mg/day 20 mg
CR Oxycodone
  • 10-20 mg q.12 h.
  • maximum 30 mg/day
Minimum 2 days, recommended: 14 days 10 mg/day NA
IR Hydromorphone
  • 1-2 mg q. 4-6 h. as needed
  • maximum 8 mg/day
7 days 1-2 mg/day 6 mg
CR Hydromorphone
  • 3 mg q. 12 h.
  • maximum 9 mg/day
Minimum 2 days, recommended: 14 days 2-4 mg/day NA