Opioid Switching

Opioid Switching

PEP Topic 
Refractory/Intractable Pain
Description 

The term opioid refers to natural, semisynthetic and synthetic medications that relieve pain by binding to opioid receptors in the nervous system. The term includes all agonists and antagonists with morphine-like activity. Opioid switching is the change from one specific opioid to a different opiod or from one administration route to another if pain control is inadequate or side effects are a problem. Opioid switching has been studied in patients with refractory cancer pain. The National Comprehensive Cancer Network (NCCN) suggests consideration of opioid rotation or switching in the case of inadequate pain control, significant adverse events, or issues such as drug cost. Switching opioid route has been examined for its effect in managing constipation.

Effectiveness Not Established

Research Evidence Summaries

Aurilio, C., Pace, M.C., Pota, V., Sansone, P., Barbarisi, M., Grella, E., & Passavanti, M.B. (2009). Opioids switching with transdermal systems in chronic cancer pain. Journal of Experimental & Clinical Cancer Research, 28, 61.

doi: 10.1186/1756-9966-28-61
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Study Purpose:

To evaluate the analgesic and side effects that result from switching between transdermal buprenorphine and transdermal fentanyl

Intervention Characteristics/Basic Study Process:

Patients had an initial screening visit so investigators could obtain historical data. Patients who met inclusion criteria returned one week later for recruitment. Each patient received a diary in which to rate pain each morning, on a visual analog scale (VAS), and in which to record use of rescue pain medication. Any patients who had taken buprenorphine 70 mcg/hour continuously during the prior week and who had suffered side effects and refractory pain had his or her patch replaced by a 25 mcg/hour transdermal fentanyl patch. The fentanyl patch was positioned at a site different from the site of the previous patch. Patients who had taken fentanyl 75 mcg/hour during the prior week and who had suffered similar side effects and pain were switched to a 52.5 mcg/hour transdermal buprenorphine patch positioned on a different skin site. Rescue medication, 20 mg immediate-release oral morphine up to three times daily, was prescribed to each patient. Patients were followed for four weeks and seen weekly in the clinic for study assessments.

Sample Characteristics:

  • The sample consisted of 32 patients.
  • Mean patient age was 62 years; age range was 42–79 years.
  • The sample was 46.8% female and 53.2% male. 
  • The sample included multiple cancer diagnoses. The most frequent diagnoses were prostate, lung, and stomach cancers.
  • Patients had chronic pain that had been treated for the previous three months; inadequate analgesia; and the presence of adverse events, such as sedation, dysphoria, nausea, vomiting, or constipation.
  • Patients were excluded from the study if they received chemotherapy or radiotherapy cycles within the study period.

Setting:

This was a single-site, outpatient study conducted in Naples, Italy.

Study Design:

The was a prospective trial.

Measurement Instruments/Methods:

  • A 100-mm visual analog scale (VAS) was used to measure pain.
  • Mean weekly ratings were recorded according to the Present Pain Intensity (PPI) scale (0 = no pain, 5 = excruciating).
  • A 15-item Pain Rating Index (PRI), adapted from the Short-Form McGill Pain Questionnaire, was used.
  • Dose of rescue pain medication taken (mg/day) was recorded.
  • Adverse events were recorded as present or absent in response to questions about nausea-vomiting, constipation, and dysphoria.
  • Level of sedation was rated on a four-point scale with 0 = no sedation and 3 = severe sedation.

Results:

  • Compared to baseline values, VAS scores decreased significantly (p < 0.0001) after each week of treatment.
  • In both groups, authors noted a significant reduction in PPI scores at each visit (p < 0.0001). At weeks 3 and 4, data regarding all patients showed a significant reduction in PRI (p < 0.0001) and a reduction in use of rescue medication (p < 0.0001).
  • The number of patients with constipation decreased. Nausea or vomiting persisted only in patients with gall bladder and gastric cancers (n = 3).
  • In both groups, dysphoria and sedation disappeared completely after the first week.

Conclusions:

Findings indicate that, by replacing burprenorphine and fentanyl transdermal delivery with a 50% reduction in the new opioid dose, investigators achieved a significant reduction in pain and the need for short-term rescue medication.

Limitations:

  • The study had a small sample size, with fewer than 100 patients.
  • The study had a risk of bias in the VAS reporting because there was no blinding.
  • Study duration was only four weeks; long-term efficacy of the intervention in the management of chronic pain management is unknown.

Nursing Implications:

This study did not use equianalgesic doses when opioids were switched. This suggests that, at least initially, lower doses of the new drug may have been effective and reduced side effects. Further studies are warranted to continue the development of safe and effective opioid-switching methods.

Mercadante, S., Ferrera, P., Villari, P., & Casuccio, A. (2005). Rapid switching between transdermal fentanyl and methadone in cancer patients. Journal of Clinical Oncology, 23, 5229–5234.

doi: 10.1200/JCO.2005.13.128
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Study Purpose:

To evaluate whether patients on either transdermal fentanyl or oral methadone required switching opioid therapy because of ineffective analgesia or adverse effects

Intervention Characteristics/Basic Study Process:

The ratio between patients receiving fentanyl and methadone was 1:20. Patients who started with fentanyl patches and were switched to oral methadone had the patch removed with the first dose of methadone (n = 24). Patients who started on oral methadone and were switched to patches received the patch immediately after the last dose of methadone (n = 7). Rescue doses of oral or IV morphine were given using 1/6 of the daily dose.

Sample Characteristics:

The study consisted of 31 consecutive patients admitted to an acute palliative care unit for a one-year period.

Setting:

The study was conducted in an acute palliative care unit in Italy.

Study Design:

This was a prospective study.

Measurement Instruments/Methods:

A switch was considered successful when the pain intensity or distress score decreased by at least 33%.

Results:

Eighteen patients benefited from switching, as confirmed by significant changes in pain intensity and distress scores. In those who switched from fentanyl to methadone, the mean time to dose stabilization was 4.3 days. In those who switched from methadone to fentanyl, mean time to stabilization was 2 days. The switch was considered unsuccessful In six patients.

Limitations:

  • Few patients switched from methadone to fentanyl.
  • The sample size was small.
  • Studying patients undergoing palliative care in critical conditions can be difficult because of complex contexts.

Nursing Implications:

Rapid titrations need to be closely monitored in an acute care setting.

Narabayashi, M., Saijo, Y., Takenoshita, S., Chida, M., Shimoyama, N., Miura, T., … Advisory Committee for Oxycodone Study. (2008). Opioid rotation from oral morphine to oral oxycodone in cancer patients with intolerable adverse effects: An open-label trial. Japanese Journal of Clinical Oncology, 38(4), 296–304.

doi: 10.1093/jjco/hyn010
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Study Purpose:

To investigate the efficacy and safety of switching from oral morphine to oral oxycodone and to evaluate this regimen in patients with renal impairment

Intervention Characteristics/Basic Study Process:

Patients were rotated from controlled-release (CR) oral morphine to oral oxycodone CR via a 3:2 ratio. Immediate-release (IR) oxycodone was used for breakthrough pain (BTP) at 1/6 of the 24-hour oxycodone dose. If pain intensity was rated as moderate to severe or if more than 3 rescue doses of IR oxycodone were administered in 24 hours, oxycodone was titrated upward. If untoward side effects were experienced, the oxycodone dose was titrated downward. Patients were deemed successful if pain control was adequate for 10 days. Pharmacokinetic evaluation for renal impairment was conducted on patients with adequate relief.

Sample Characteristics:

  • The sample consisted of 25 patients.
  • Mean age was 62.8 years (SD = 11.6 years).
  • The sample was 24% female and 76% male.
  • Cancer diagnoses included lung, breast, and pancreas.
  • All patients were receiving morphine for cancer pain and were either having difficulty controlling pain with morphine or had intolerable side effects.

Setting:

This study was a multisite, outpatient setting study conducted at 14 sites in Japan.

Study Design:

This was a multicenter, open label, dose-titration study.

Measurement Instruments/Methods:

  • Pain control rate (i.e., the rate in which patients achieved stable and adequate pain control) was defined as CR oxycodone unchanged for 48 hours or more, slight or no pain intensity, fewer than two rescue doses in 24 hours, and tolerable side effects.
  • A 0–100 mm pain intensity visual analog scale (VAS) was used with every administration. 
  • Categorical acceptability was rated on a scale from 1 (very poor) to 5 (excellent).
  • Safety was evaluated based on frequency, severity, seriousness, causality, and tolerability of adverse events.
  • Serum creatinine and creatinine clearance were measured.

Results:

  • The study yielded an adequate pain control rate of 84%, and time to adequate relief was 2.3 days.
  • Pain intensity at study entry was 1.9 (moderate pain). Intensity significantly decreased by the end of the study (p < 0.0001).
  • Average VAS went from 53.5 mm at study entry to 27.6 mm at study end (p < 0.0001).
  • Acceptability was rated as very poor (12%) to poor (64%) at the beginning of the study. At end, acceptability was rated as very poor (8.3%), poor (16.7%), fair (45.8%), and good (29.2%). Mean acceptability was 2.1 at entry and 3.0 at end (p = 0.0004).
  • Nausea was rated 2.3 with morphine and decreased to 0.4 with oxycodone (p = 0.0005), drowsiness went from 2.1 to 0.9 (p = 0.0313), vomiting went from 2.2 to 0.2, and constipation went from 2.2 to 1.6.
  • M3G and M6G metabolites were increased at study initiation in patients with renal compromise; oxycodone metabolites were not increased in patients with renal compromise at the end of the study.

Conclusions:

Rotation to oral oxycodone for patients who had inadequate pain control or significant adverse events with morphine was successful. Retention of oxycodone metabolites did not seem to exist in patients with renal compromise.

Limitations:

  • The sample size was small, with fewer than 30 patients.
  • The sample was not randomized, there was no control, and it was a convenience sample.
  • Assessment for adverse events was subjective.

Nursing Implications:

Oxycodone can be recommended as an alternative to morphine, and patients may experience fewer adverse events with oxycodone. Patients with renal compromise may benefit from oxycodone over morphine as morphine contributes to metabolite accumulation, leading to potential oversedation or adverse events.

Oldenmenger, W.H., Lieverse, P.J., Janssen, P.J., Taal, W., van der Rijt, C.C., & Jager, A. (2012). Efficacy of opioid rotation to continuous parenteral hydromorphone in advanced cancer patients failing on other opioids. Supportive Care in Cancer, 20, 1639–1647.

doi: 10.1007/s00520-011-1254-1
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Study Purpose:

To describe the analgesic efficacy and side effects of parenteral hydromorphone among patients with severe cancer-related pain

Intervention Characteristics/Basic Study Process:

Medical records were reviewed and data were collected retrospectively for patients admitted to a palliative care unit for pain management because of uncontrolled pain or severe side effects from their current pain regimens. Patients were started on parenteral hydromorphone. After starting the intervention, pain intensity and side effects were recorded twice daily. All patients had previously received opioids.

Sample Characteristics:

  • N = 104      
  • MEAN AGE = 57 years (SD = 13.5 years)
  • MALES: 55%, FEMALES: 45%
  • KEY DISEASE CHARACTERISTICS: 88% had metastatic disease and nociceptive pain
  • OTHER KEY SAMPLE CHARACTERISTICS: Some patients were receiving chemotherapy or palliative radiation therapy. Some patients also were receiving ketamine during the study. Eighty-eight percent had had two or more previous opioid rotations. Median effective dose was 600 mg per day (range = 72–2592 mg per day).

Setting:

  • SITE: Single site    
  • SETTING TYPE: Inpatient    
  • LOCATION: Netherlands

Phase of Care and Clinical Applications:

  • PHASE OF CARE: End-of-life care
  • APPLICATIONS: Palliative care

Study Design:

  • Retrospective, descriptive

Measurement Instruments/Methods:

  • Numeric rating scale for pain
  • Effectiveness determined as change in mean pain intensity at rest and with movement
  • Time of adequate control was defined as first of at least two consecutive days with mean pain score of 4 or less, or physician was satisfied that pain was controlled

Results:

Adequate pain control was reported for 83% of patients, and among those who had improvement, the decline in mean pain score was significant (p < .001), ranging from a 2.7–3.1-point reduction. Seventeen percent had no response. Survival analysis showed continued effect of hydromorphone for 150 days for those who continued on the study (35 patients).

Conclusions:

Switching to parenteral hydromorphone was effective for pain control in some patients who had either uncontrolled pain or severe side effects with previous pain medication regimens.

Limitations:

  • Baseline sample/group differences of import
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Risk of bias(sample characteristics) 
  • Unintended interventions or applicable interventions not described that would influence results
  • Key sample group differences that could influence results
  • Measurement/methods not well described
  • Measurement validity/reliability questionable
  • Other limitations/explanation: Differences in pain scores were used to show statistical significance, but the timing of measures used is not described, and authors state that where measurements were not available, physician satisfaction with control was used to show efficacy. It was stated that some patients were on ketamine, but it was not clear how much, who, or the potential impact on findings. A variety of coanalgesics were used, with no relevant subgroup analysis. There was extreme variability in baseline opioid dosages, suggesting highly varied baseline pain levels as well–range of baseline levels is not provided. Some patients also were receiving other palliative therapies, and analysis did not consider this.

Nursing Implications:

Findings suggest that opioid rotation to parenteral hydromorphone was effective for some patients who had either uncontrolled pain or unacceptable opioid side effects. This study provides rather weak evidence because of numerous study limitations, but, for those patients at the end of life with intractable pain or significant adverse effects on current pain regimens, alternative approaches that may be effective are important to consider. Parenteral hydromorphone may be an appropriate alternative for these patients.

Reddy, A., Yennurajalingam, S., Pulivarthi, K., Palla, S.L., Wang, X., Kwon, J.H., . . . Bruera, E. (2013). Frequency, outcome, and predictors of success within 6 weeks of an opioid rotation among outpatients with cancer receiving strong opioids. The Oncologist, 18, 212–220.

doi: 10.1634/theoncologist.2012-0269
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Study Purpose:

To determine indications, results, and predictors of successful opioid rotation

Intervention Characteristics/Basic Study Process:

Records of consecutive patients who received strong opioids and had follow-up data within six weeks of the initial clinic visit were reviewed and analyzed.

Sample Characteristics:

  • N = 146 patients with six weeks of data; 114 had opioid rotation
  • MEDIAN AGE = 55 years
  • MALES: 60%, FEMALES: 40%
  • KEY DISEASE CHARACTERISTICS: Multiple tumor types
  • OTHER KEY SAMPLE CHARACTERISTICS: 71% Caucasian, 12% African American, 11 % Hispanic

Setting:

  • SITE: Single site 
  • SETTING TYPE: Outpatient 
  • LOCATION: Texas

Phase of Care and Clinical Applications:

  • APPLICATIONS: Palliative care

Study Design:

  • Retrospective, descriptive

Measurement Instruments/Methods:

  • Edmonton Symptom Assessment Scale
  • Symptom Distress Scale
  • Delirium Assessment Scale
  • Cut down, annoyed, guilty, eye-opener (CAGE) questionnaire

Results:

Successful opioid rotation was defined as improvement in side effects if that was the reason for opioid rotation, or a 30% or 2-point reduction in pain if uncontrolled pain was the reason for opioid rotation. For 95% of patients, uncontrolled pain was the reason for opioid rotation. Sixty-five percent of patients had successful opioid rotation.  No difference was seen in success based on ethnic and demographic data. Scores for pain (p < .001), insomnia (p = .013), and depression (p = .04) were improved at follow-up, with no significant difference in morphine equivalents at follow-up.

Conclusions:

Findings suggest that opioid rotation is successful in some patients for improvement in pain management.

Limitations:

  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)

 

Nursing Implications:

Opioid rotation has been suggested in cases of uncontrolled pain for individuals on strong opioids, but little research has been done in this area. This study is purely descriptive, but does suggest that opioid rotation can be successful to improve pain control for some patients.

Guideline/Expert Opinion

National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Adult cancer pain [v. 2.2011]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf

http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf
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Type of Resource/Evidence-Based Process:

These guidelines do not provide any information about search strategy or any specific evaluation of evidence. Notes state that most direct evidence is of low quality, but recommendations do result from unanimous consensus.

Guidelines & Recommendations:

The guidelines provide detailed recommendations regarding:

  • Screening and assessment
  • Management of pain in opioid-naive as well as opioid-tolerant patients
  • Ongoing care of adult patients with cancer and related pain management
  • Comprehensive pain assessment and use of pain ratings
  • Interventions for specific types of pain syndromes
  • Opioid prescribing, titration, and ongoing management
  • Management of adverse effects related to opioids
  • Psychosocial support and patient and family education
  • Nonpharmacologic interventions.

Limitations:

In general, opioids are first-line interventions. The NCCN guidelines suggest that antidepressants and anticonvulsants can be first-line treatments for adjuvant pain, although the recommendation for using them as such is still based on anecdotal experience or guidelines relating to patients who do not have cancer.

Nursing Implications:

The NCCN guidelines provide comprehensive algorithms for pain management, from screening to ongoing maintenance. The guidelines recommend considering a variety of nonpharmacologic interventions. Psychosocial support, including coping-skills training, is recommended, as is comprehensive patient and family education. The guidelines provide useful information and an overview of the full range of pain management. The work points to the ongoing need to consider multiple adjuvant and supportive interventions to achieve pain relief that works for the individual patient.


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