Greenwald BD, Narcessian EJ. J Pain Symptom Manage 1999; 17(5): 369-375.

Prepared by: : Manju Chandra, Pharmacy Intern

Received during: Journal Rounds, Tertiary Palliative Care Unit

Abstract:

Background: Previous studies of pharmacists have suggested poor availability of opioids and apprehension about dispensing these drugs. This pilot study was designed to determine pharmacist's knowledge and attitudes regarding the use of opioids in chronic cancer and noncancer pain patients, quantify the resistance to stocking and dispensing opioids, and determine the availability of opioid analgesics for patients with chronic pain.
Methods: Fifty-two randomly selected New Jersey retail community pharmacies were recruited. A 19-question survey developed by the Kessler Pain Management Group was administered containing questions about opioids that are regularly stocked, issues regarding morphine dosing, definition of addiction as well as perceived prevalence of addiction, and perceived legality of certain prescribing scenarios. A cover letter was sent with the survey explaining the survey and the procedure to return it. Two weeks after the mailing, one additional call was made to all nonresponders.
Results: Of the 52 surveys faxed or mailed, 36 (69%) were returned and analyzed. Most of common opioids used for pain management were stocked by 80% or greater of respondents. The highest daily dose of oral morphine that respondents had dispensed ranged from 60mg/day to 2000mg/day with an average of 254.5mg/day (SD=344.1). The highest daily dose or oral morphine that respondents had heard of ranged from 60mg/day to 5000mg/day with an average of 737.4mg/day (SD=1042.0). The highest daily dose of morphine that respondents were comfortable dispensing ranged from 60mg/day to 2000mg/day with an average of 411.2mg/day (SD=522.6). Thirty three percent (12/36) of respondents believed that a patient, regardless of diagnosis, will become addicted if an opioid is taken on a daily basis for one month. Thirty six percent (13/36) believed that it is illegal for a physician to prescribe methadone for pain unless he/she is certified in addiction medicine. Methadone was stocked by only 16.6% of respondents. Thirty six percent (13/36) answered that they would be resistant to fill prescriptions from a single doctor for more than one opioid at a time. Forty two percent (15/36) of respondents answered that the meaning of "addiction" was physical dependence, tolerance, and psychological dependence, 17% (6/36) answered physical and psychological dependence, 25% (9/36) answered physical dependence, and 11% (4/36) answered psychological dependence. In the scenario of cancer pain, 75% of respondents thought prescribing opioids for several months was both lawful and generally acceptable medical practice. However, in the scenario of cancer pain with a history of substance abuse, only 36.1% felt it was lawful and acceptable medical practice.
Conclusions: Reinterpretation of intended treatment by pharmacists may have an impact on the patient outcome. In this study, the respondent's answers to questions reflect the common myths and misconceptions pharmacists may have. They should not fear dispensing opioids for a legitimate medical purpose. Pharmacists would benefit from education regarding issues related to the use of opioids for chronic pain. This is vital so that pharmacists can continue to make a positive impact and play an important role in the multidisciplinary care of patients with chronic pain.

Comments:

Strengths/uniqueness:
This report includes a review of past literature and explored many barriers that play a role in providing effective care for patients. The paper suggests effective ways in which misconceptions may be cleared.

Weaknesses:
The size of the study was small, which may limit its generalizability. It also only included community pharmacies that may not be serving the population requiring the highest doses of opioids.

Relevance to Palliative Care:
Many patients requiring palliative care will be in the community with regular contact with their pharmacist. This report is useful in assessing attitudes which may be present and that may represent barriers. It provides a window into the concerns and misconceptions pharmacists may have and suggests interventions that may be made. Addressing issues in this report will allow a more understanding pharmacist-patient relationship to be made and effective patient care.

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center.

Kloke M, Rapp M, Bosse, Kloke O. Support Care Cancer 2000; 8:479-486.

Prepared by: : Dr. Robin Fainsinger

Received during: Journal Rounds on the Tertiary Palliative Care Unit, Grey Nuns Hospital

Abstract:

The charts of 273 cancer patients were retrospectively analyzed in order (1) to evaluate the frequency of opioid change (OCH) when adjuvants (antiemetics/laxatives) were administered on a regular basis and co-analgesic medication as indicated by the specific type of pain, (2) to define risk factors for the request of OCH, and (3) to reveal settings in which OCH may not be recommended as a first-line therapeutic intervention. Opioids used included morphine, fentanyl, 1-methadone, and buprenorphine. Out of 273 patients, 103 changed opioids at least once, with a success rate of 65%. The indications for the OCH were insufficient analgesia in 43%, intolerable side effects in 20%, both in 15%, and other reasons in 22% of patients. The frequency of OCH was not influenced by the routine use of adjuvants or co-analgesics except corticosteroids, which raises queries about the concept of an opioid-sparing effect of co-analgesics. The occurrence of intolerable side effects is thought not to be dose dependent so much as to reflect differences in the individual tolerability of a distinct opioid for whatever reason (genetically fixed or individually acquired pharmacodynamic or kinetic properties). Moreover, there was strong evidence for the existence of an unpredictable and incomplete cross-tolerance between opioids, which meant careful titration of the new opioid was required after COH. The overall frequency of OCH was similar to that observed in previous studies in spite of the documented addition of adjuvants and co-analgesics. This retrospective study supports the notion that opioid rotation must be retained as an essential therapeutic option even with optimized adjuvant and co-analgesic regimens.

Comments:

Strengths/uniqueness: A large study of 273 consecutive patients. Single external reviewer lessens the bias of the chart review process.

Weaknesses: The authors fail to describe the many weaknesses inherent in their retrospective study, that inevitably limit the value of their conclusions

Relevance to Palliative Care: This report is a valuable addition to the increasing literature on the controversy of sequential opioid trials. The conclusion raising the question of the true opioid sparing effect of adjuvant analgesics should encourage further research in this area.

Opioid-induced hyperalgesia: a qualitative systematic review. Downloadable PDF File

Angst MS, Clark JD. Anesthesiology 2006; 104:570-87.

Prepared by: Dr. Sharon Watanabe

Presented at: Journal Club (UAH, RAH, CCI)

Abstract: Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

Comments:

Strengths/Uniqueness: This paper represents an admirable attempt to summarize a large body of evidence from disparate sources on a very complex topic. The search strategy and inclusion criteria are well described.

Weaknesses: The article does not mention the experimental and clinical evidence for the role of opioid metabolites in the development of opioid-induced hyperalgesia (OIH). Also, a more detailed discussion of peripheral and central sensitization to chronic pain as a factor in increased pain perception would have been appropriate, since some of the underlying mechanisms are in common with those for OIH.

Relevance to Palliative Care: Despite abundant animal data, there is limited evidence to confirm the existence of clinically relevant opioid-induced hyperalgesia (OIH). Perhaps the most compelling evidence comes from case reports of patients with allodynia on high dose opioids. Strategies to address OIH include opioid dose reduction, opioid rotation, and possibly the use of NMDA antagonists. Available evidence suggests that phenantrene opioids (e.g. morphine, hydromorphone, oxycodone) may be more likely to cause OIH than piperidine opioids (e.g. fentanyl) or methadone. In the situation of pain that fails to respond to increasing doses of opioid, it would be reasonable to include OIH in the differential diagnosis, along with opioid tolerance, peripheral and central sensitization, delirium, somatization of psychological distress, and addiction.

Opioids and the immune system. (downloadable pdf file)

Sacerdote, P. Palliat Med 2006; 20:S9-S15.

Prepared by: Shahram Jabbari

Received during: Journal Rounds on the Tertiary Palliative Care Unit, July 26, 2006

Abstract

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent µ-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression, induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.

Comments

Strengths/uniqueness:
Draws attention to an understudied aspect of pain control.

Weaknesses:
Article still mainly relies on animal studies.
It does not discuss the role of tolerance to immunosuppression. We know that many opioid users are chronic users and the role of tolerance must be considered more seriously.

Relevance to Palliative Care:
The significance of the immunosuppressive effect of opioids in palliative care medicine and the relevance to every day practice remain unclear. It is possible that future research may suggest advantages for some opioids over others due to different effects in the immune system.
This article should not prompt a change in opioid prescribing practices, as buprenorphine is not a recommended opioid for cancer pain.