June 2006

PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care) provides palliative care clinicians with concise summaries of the most important findings from more than 30 medical and scientific journals. Share PC-FACS with your colleagues during this trial period and encourage them to sign up for a complimentary subscription here. Comments from readers are welcomed at resources@aahpm.org.

Surrogate Decision-Makers

Accuracy of Surrogate Decision-Makers

Background: When patients are incapacitated, clinicians rely on patient-designated or next-of-kin surrogates to make treatment decisions. These individuals are instructed to operate under the substituted judgment standard, which asks that they make the same decision that the patient would have made. Do surrogate decision-makers accurately predict patients’ end-of-life preferences?

Design and Participants: A systematic literature search identified studies that evaluate the accuracy of surrogate decision-making as well as the efficacy of interventions designed to improve that accuracy. Sixteen studies met inclusion criteria, involving 151 hypothetical scenarios and 2,595 surrogate-patient pairs. Included studies represented different populations, including terminally ill patients, hospital outpatients, chronically ill patients, and elderly female patients. Two authors extracted the data describing the hypothetical scenarios as well as the data detailing the accuracy of prediction by surrogates. Meta-analysis was performed.

Results: Surrogate predictions were correct 68% (95% CI, 63-72) of the time. Predictions were most accurate when scenarios involved a patient’s current health (79%; 95% CI, 74-83) or the use of antibiotics (72%; 95% CI, 66-77) and were least accurate when scenarios involved dementia (58%; 95% CI, 52-64) or stroke (58%; 95% CI, 52-64). Both patient-designated and legally-assigned surrogates predicated preferences with equivalent accuracy (69% and 68% accuracy, respectively) and the surrogate’s relationship to the patient was not correlated with accuracy. Two studies suggested that predictions were not improved by discussion of patient preferences. Four studies confirmed that surrogate predictions were more accurate than physician predictions.

Commentary: Surrogate decision-makers provide critical input in end-of-life decisions. While the ideal world would include clear details on patient wishes for every eventuality, this is not practical or realistic. Unfortunately, surrogates provide inaccurate advice in a third of cases. Further, this study suggests that two of the methods we rely on most commonly to improve decision-making are not very useful. Patient-designated surrogate decision-makers were not more accurate than legally-assigned decision-makers. Prior discussions between surrogates and patients about end-of-life care did not improve accuracy either. Still surrogates are better than physicians. I question how closely the predictive accuracy estimated using hypothetical scenarios approximates what occurs in actual cases (e.g., how does the emotion encountered during real end-of-life scenarios influence actual predictive accuracy?), but measurements during actual cases are not practical. Clearly we have work to do in developing new methods to help surrogates best understand and advocate for patient preferences for end-of-life care.

Bottom Line: In this systematic review of studies using hypothetical scenarios, surrogates provide accurate estimates of patients’ end-of-life treatment preferences approximately two-thirds of the time.

Reviewer: Amy P. Abernethy, MD, Duke University Medical Center

Source: Shalowitz DI, Garrett-Mayer E, Wendler D. The accuracy of surrogate decision makers: a systematic review. Arch Intern Med. 2006 Mar 13;166(5):493-7. PMID: 16534034. To access the abstract of this article, link to NLM – PubMed here.

Morphine Tolerance

Orphanin FQ/Nociceptin and Morphine Tolerance

Background: Development of morphine tolerance can complicate the long-term treatment of chronic or severe pain. Orphanin FQ/nociceptin (OFQ/N) is a neuropeptide known to counteract several effects of exogenous and endogenous opioids. Is OFQ/N involved in the development of morphine tolerance and dependence?

Design and Participants: OFQ/N was evaluated from both genetic and pharmacologic perspectives with the intent of determining what role, if any, it plays in the development of morphine tolerance. OFQ/N wild-type and knockout mice were injected with increasing doses of morphine to evaluate for a difference in the acute analgesic effect. Animals were subsequently injected with low doses of morphine daily for 22 days and observed for development of tolerance. Finally, C57BL/6N mice were co-injected with low doses of morphine and a synthetic NOP antagonist (J-113397) daily for 22 days and observed for development of tolerance.

Results: There was no difference in acute analgesic effect between OFQ/N wild-type mice and OFQ/N knock-out mice, suggesting that OFQ/N is not involved in acute analgesia. OFQ/N wild-type mice developed tolerance within 7 days of the initiation of daily morphine injections while this response was attenuated in OFQ/N knockout mice, suggesting that OFQ/N modulates the development of tolerance. The C57BL/6N mice that were co-injected with morphine and J-113397 failed to develop tolerance over a period of 3 weeks, suggesting that blockade of OFQ/N signaling can prevent development of morphine tolerance.

Commentary: Prolonged opioid exposure produces counter opioid responses, analgesic tolerance, and even opioid facilitated pain and loss of analgesia through release of modulator proteins. Nociceptin is released through generation of prostaglandins and binds to orphanin receptors [N/OFQ-NOP]. Dynorphin is released in the spinal cord and binds to kappa receptors and activates NMDA receptors. Activation of these receptors leads to hyperalgesia and lower pain thresholds. ^{1, 2} Rotation to buprenorphine will reverse opioid tolerance and hyperalgesia more than improve analgesia by blocking kappa receptors.³ NSAIDS prevent the release of nociceptin and thus are opioid-dose sparing.⁴

Bottom Line: These basic scientific data support the clinical observation that the loss of analgesia with chronic opioids is re-established by blocking or reversing counter opioid responses.

Reviewer: Mellar P. Davis, MD FCCP, Cleveland Clinic

Source: Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK. Endogenous orphanin FQ / nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther. 2006 Apr 4; [Epub ahead of print] PMID: 16595734. To access the abstract of this article, link to NLM – PubMed here.

References:
1. Cesselin F. Opioid and anti-opioid peptides. Fundam Clin Pharmacol 1995. 9:40-433.
2. Gardell LR, King T, Ossipov MH, Rice KC, Lai J, Vanderah TW, Porreca F. Opioid receptor mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neuroscience Letters 2006; 44-49.
3. Okuda-Ashitaka E, Matsumura MT, Takeshima H, Reinschied RK, Civelli O, Ito S. The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury. Eur J Neurosci 2006; 23:995-1004.

Oxycodone for Cancer Pain

Oxycodone for Cancer Pain

Background: Is oxycodone effective in relieving cancer-related pain and what adverse effects are associated with its use?

Design and Participants: A literature search designed to identify randomized controlled trials comparing oxycodone to placebo or another active analgesic drug in patients with cancer-related pain was performed. Studies using combination oxycodone preparations were excluded. Only 4 studies were adequate to be included in the meta-analysis (oxycodone vs morphine n = 3; oxycodone vs hydromorphone). Differences in pain scores were expressed as standardized weighted mean differences for the purposes of meta-analysis. Data on adverse effects were also collected.

Results: Mean pain scores did not differ between oxycodone and control medications (pooled standardized mean difference [SMD], 0.04; 95% CI -0.29 to 0.36; p=0.8). When comparing oxycodone to morphine, pain scores were higher with oxycodone (0.20; 95% CI, −0.04 to 0.44). When comparing oxycodone to hydromorphone, pain scores were lower with oxycodone (−0.36; 95% CI, −0.71 to 0.00). As many as 90% of patients in each trial experienced opioid-related adverse events; the overall discontinuation rate was 13% (29/222). Overall, there was no significance difference in the development of nausea (odds ratio [OR] 0.75; 95% CI, 0.51-1.10) or vomiting (OR 0.72; 95% CI, 0.49-1.06), though there did appear to be a trend favoring oxycodone. In trials comparing oxycodone with morphine, patients receiving oxycodone experienced less dry mouth (OR 0.56; 95% CI, 0.38-0.83) and there was a trend toward less drowsiness (OR 0.72; 95% CI, 0.47-1.1).

Commentary: This review of oxycodone effectiveness shows that opioids improve pain and frequently cause adverse effects in cancer patients. It has some limitations: a) lack of intention to treat analysis, b) no masking of outcome assessors, c) short duration of treatment (20 days), d) few primary trials (n=4) of small size assessing effectiveness.  Clinically, this study supports the use of oxycodone as an effective alternative in patients for whom morphine is not adequate. I believe these patients are similar to those that I see. Given the relative cost of oxycodone vs. morphine and more data about effectiveness of morphine, I expect to continue using morphine for first-line pain management.  Systematic assessment and aggressive management of opioid-related adverse effects is emphasized.

Bottom Line: This systematic review of good quality demonstrates that oxycodone is as effective as other opioids, particularly morphine, for the short-term treatment of cancer-related pain in outpatients.

Reviewer: David Nowels, MD MPH, University of Colorado Health Sciences Center

Source: Reid CM, Martin RM, Sterne JA, Davies AN, Hanks GW. Oxycodone for cancer-related pain: meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Apr 24 166(8):837-43. PMID: 16636208. To access the abstract of this article, link to NLM – PubMed here.

Pyridostigmine and Orthostasis

Pyridostigmine for Neurogenic Orthostatic Hypotension

Background: Orthostatic hypotension (OH) can result from disease involving the neural pathways of the baroreflex. A placebo-controlled trial demonstrated improvement of OH with midodrine hydrochloride but with significant worsening of supine hypertension. Does pyridostigmine bromide improve OH without affecting supine blood pressure (BP)?

Design and Participants: This double-blind, randomized, study was described as a 4-way crossover trial, but details of the crossover methods are not available. The study compared the effects of placebo, 60 mg of pyridostigmine bromide, 60 mg of pyridostigmine bromide plus 2.5 mg of midodrine hydrochloride, and 60 mg of pyridostigmine bromide plus 5 mg of midodrine hydrochloride given on sequential days. Eligible patients had neurogenic OH, defined as a systolic BP reduction of ≥30mmHg or a mean BP reduction of ≥20mmHg occurring within 3 minutes of standing. The primary end point was improvement in standing diastolic BP fall 1 hour after drug administration. Secondary end points included influence on systolic and supine BP, relationship to symptoms, predictors of response, and influence on plasma neurotransmitters. Mean age of participants was 59 (SD 11) years and all patients had severe generalized autonomic failure.

Results: 58 patients were randomized. Overall, there was a statistically significant reduction of the fall in standing diastolic BP with treatment (p = 0.02). Pyridostigmine alone (BP fall of 27.6 mmHg) and pyridostigmine plus 5 mg midodrine hydrochloride (BP fall of 27.2 mmHg) demonstrated benefit when compared to placebo (BP fall of 34.0 mmHg; p = 0.04 and p = 0.002, respectively). There were no significant differences in supine systolic or diastolic BP (p = 0.36 and p = 0.85, respectively). The reduction in fall in standing diastolic BP was associated with improved symptoms.

Commentary: The paucity of available treatments for OH and the aggravation of supine hypotension currently limit clinicians’ options. The suggested benefit of pyridostigmine for OH is intriguing, however the many problems with this study and its published report decrease my enthusiasm for the results. The patient numbers initially suggest low statistical power to detect differences between the intervention groups, but the crossover design described in the introduction would have improved this dramatically. Unfortunately, it is not clear how or if the crossover was performed. Elements of the results suggest a crossover methodology (e.g., numbers in tables, analysis plan) but, if true, then there was an apparent 25-30% unexplained drop-out rate. Midodrine has an incidence of 18% parathesias and pyridostigmine has a number of significant cardiovascular and central nervous system side effects. However no side effects were mentioned in this study. Finally, the authors do not describe any potential or actual study weaknesses in their conclusion. Although this article has significant weaknesses, it is still a very interesting piece. Past treatments aggravate supine hypertension; however, data from this study suggests that a combination of mechanisms including acetylcholinesterase inhibition and alpha adrenergic antagonism improves OH and does not increase supine hypertension.

Bottom Line: Pyridostigmine is another potential treatment for OH, a difficult and distressing problem. However, multiple study weaknesses limit the usefulness of these data. It is important for palliative care specialists to be aware of study flaws that can limit the usefulness of published results.

Reviewer: John Peppin, DO FACP, Iowa Pain Management Clinic, Des Moines, Iowa

Source: Singer W, Sandroni P, Opfer-Gehrking TL, Suarez GA, Klein CM, Hines S, O’Brien PC, Slezak J, Low PA. Arch Neurol. 2006 Apr;63(4):513-8. Epub 2006 Feb 13. PMID: 16476804. To access the abstract of this article, link to NLM – PubMed here.

© 2006, American Academy of Hospice and Palliative Medicine. All rights reserved. No part of this publication may be reproduced without the express written permission of AAHPM.

PC-FACS is edited by Amy Abernethy, MD, of Duke University Medical Center. AAHPM thanks the following Associate Editors for their review of the critical summaries and preparation of the commentaries:

Robert M Arnold, MD
Stephen Bekanich, MD
Janet Bull, MD
Ira Robert Byock, MD
Ronald J Crossno, MD CMD FAAHPM
Mellar P Davis, MD FCCP
Betty Ferrell, PhD RN FAAN
Perry G Fine, MD
Daniel Fischberg MD PhD
Gail Gazelle, MD FACP FAAHPM
Laura Hanson, MD MPH
John F Manfredonia, DO
Gregory J Miller, MD
Alan Nixon, MD
David Nowels, MD
John Peppin, DO FACP
Brad Stuart, MD
James A Tulsky, MD
Joanne Wolfe, MD
Donna S Zhukovsky, MD FACP

The views expressed herein are those of the individual authors and are not necessarily those of the Academy. Information included herein is not medical advice and is not intended to replace the judgment of a practitioner with respect to particular patients, procedures, or practices. To the extent permissible under applicable laws, the Academy disclaims responsibility for any injury and/or damage to persons or property as a result of any actual or alleged libelous statements, infringement of intellectual property or other proprietary or privacy rights, or from use or operation of any ideas, instructions, procedures, products or methods contained in this publication.