Wiffen, P.J., & McQuay, H.J. (2010). Oral morphine for cancer pain. Cochrane Database of Systematic Reviews 2010(8).

To determine the efficacy of oral morphine in bringing relief from cancer pain; to assess the incidence and severity of side effects associated with oral opioids

• Databases searched were MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL); Cochrane Pain, Palliative and Supportive Care Group Trials Register; and Oxford Pain Relief Database. In addition, investigators performed manual searches of 40 key journals that list pain-related trials.
• Search keywords were analgesics, opioid (*administration and dosage), morphine, (*administration and dosage), neoplasms (*complications) pain (*drug therapy, radiotherapy), randomized controlled trials (RCT). Investigators searched for studies relating to humans, adults, and children.
• Studies were included if they
  • Were RCTs.
  • Had been published as full journal articles.
  • Compared an oral morphine preparation to placebo, active control, or alternative route of morphine.
  • Included adults or children with cancer pain that required opioids for treatment.
• Studies were excluded if they were quasi-randomized studies, included 10 or fewer participants, did not assess pain as an outcome measure, focused on pain unrelated to cancer.

The search retrieved 133 studies; 62 met inclusion criteria. After elimination of duplicates, the group for analysis included 54 studies. There were insufficient data to perform meta-analysis. Study quality was evaluated using the Jadad scale. Overall, the quality of studies was high, with a median score of 4 on a five-point scale. Studies included comparisons of modified- and immediate-release opioids, comparisons of morphine versus other drugs, and comparisons of the effects of morphine delivered by different routes and delivery mechanisms.

The 54 studies involved a total sample of 3,749 participants. Sample range was 11–699.

• Fifteen studies compared modified-release morphine to immediate-release morphine. The trials showed that both forms were similar in terms of pain relief provided and adverse effects experienced.
• Twelve studies compared various doses or dose intervals of modified-release morphine. The trials revealed no significant differences across products in terms of pain intensity, rescue analgesia, or adverse effects.
• Thirteen studies compared modified-release morphine with other opioids, including oxycodone, hydromorphone, transdermal fentanyl, dextropropoxyphene, tramadol, and methadone.
  • Comparisons of modified-release morphine with oxycodone showed that both resulted in adequate analgesia. Studies revealed some differences in side-effect profiles.
  • In a comparison of modified-release hydromorphone and modified-release morphine, both achieved satisfactory pain control. Authors noted no difference regarding the use of rescue medications.
  • Comparisons of oral morphine and transdermal fentanyl showed no significant differences between treatments in regard to pain control. However, more patients receiving fentanyl required upward-dose titration and more rescue medication. Transdermal fentanyl was associated with less sedation and less constipation. Dose-equivalency determination appeared to be problematic in one trial.
  • One small study found that, compared with morphine, dextropropoxyphene was associated with fewer side effects and lower doses needed for pain relief
  • One study of tramadol versus morphine in opioid-naive patients revealed that both medications resulted in satisfactory analgesia but that tramadol was more effective in treating neuropathic pain.
  • One study, which compared methadone to oral morphine, showed that a greater number of adverse events were associated with methadone than with oral morphine.
• Six studies compared immediate-release morphine to other opioids, including Brompton cocktail, methadone, tramadol, oxycodone, and oral transmucosal fentanyl citrate.
  • Comparisons of oral morphine to Brompton cocktail showed no difference between treatments and demonstrated that cocaine did not enhance analgesia.
  • One comparison involving morphine and methadone showed that both drugs achieved pain control but that more patients on morphine complained of dry mouth and that more patients on methadone complained of headache.
  • Tramadol and morphine use resulted in a pain decrease to similar intensities.
  • One study, which compared morphine to immediate-release oxycodone, revealed that the two achieved similar control of pain. The most frequent side effect of both was sedation. Oral morphine was associated with more nausea than was oxycodone.
  • In one study, patients could use either morphine capsules or oral transmucosal fentanyl (OTFC) for breakthrough pain. OTFC was more successful than morphine at reducing pain intensity, and the majority of patients preferred OTFC.
• The studies showed no significant difference in pain control or adverse events between oral and rectal administration or between tablets and oral suspension.
• Compared to naproxen, morphine was associated with greater use of rescue medication.
• The studies showed that oral morphine and epidural morphine produced a similar level of pain relief. The epidural route was associated with fewer side effects but more technical problems.
• Oral morphine and morphine suppositories provided a similar level of pain control. Studies showed no difference in the adverse effects associated with these two interventions.
• Various studies compared different medication routes or morphine to nonopioids. Across studies there was a 6% withdrawal rate due to adverse effects.

The literature demonstrates the effectiveness of morphine with titration to effect. The range of doses used in studies varied widely, with the maximum dose recorded being 2000 mg/day. Mean daily dose was 110–250 mg/day. This shows effectiveness over a wide range and that oral morphine, at the correct dose for the individual, is as effective as other opioids and morphine adminstered through nonoral routes. Limited evidence shows that transdermal fentanyl is faster than oral morphine at dealing with breakthrough pain. Some evidence shows that transmucosal fentanyl may be superior to oral morphine in the treatment of breakthrough pain and that fentanyl patches are associated with fewer side effects at the same level of analgesia. Oxycodone, hydromorphone, and morphine provide comparable pain control and are associated with similar adverse events. A small number of patients appear to develop intolerable side effects as the result of using oral opioids. Findings support the effectiveness of various forms of opioids for pain control, and the appropriateness of dose titration across a wide range, with specific medication selected according to each patient's responses and preferences.

These findings show that titrating to pain relief, using modified-release opioids, is possible.