Volume 1 “The effects of morphine and oxycodone on memory in humans” James Friswell D.Clin.Psy. thesis (Volume 1), 2006 University College London UMI Number: U591992 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U591992 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Overview The side effects of opiates are an important area of study as detriments to activities of daily living and to quality of life might outweigh detriments caused by untreated pain. Furthermore there has been relatively little research into the cognitive effects of opiates. This thesis aims to explore the effects of morphine and oxycodone on memory. Part one of the thesis comprises a literature review of the cognitive effects of opiates. It presents an overview of the current levels of understanding as well as highlighting the clinical importance of furthering our understanding. It also briefly raises the question of how gender may interact with the drug effects. Part 2 comprises the empirical paper. It reports a randomised, placebo-controlled, double-blind study comparing the effects of lOmg morphine, 5 mg oxycodone and placebo on 18 healthy volunteers. The findings were that these doses did not produce significant impairments in most cognitive measures, and there was no retrograde memory impairment as was seen in a previous similar study involving cancer patients. It found some subtle drug effects on working memory, episodic memory and subjective experiences. More importantly, it revealed some subtle interactions of gender and weight with drug implying that the current practice of prescribing doses of oral opiates that are not determined by weight and gender may be inappropriate. Part 3 comprises a critical appraisal of the research. It includes a description of my personal experience during the research process as well as exploring further issues of validity within the study. Table of Contents Page Part 1: Literature Review 1 Abstract 2 1. Introduction 3 2. Why is it important to study the effects of opiates? 3 2.1 Clinical use of opiates 3 2.2 Recreational and dependent use of opiates 7 3. Evidence from pre-clinical studies 7 4. A review of the effects of opiates 9 4.1 Methodological issues 9 4.2 Zacny’s (2005) review of the effects of opioids on 10 psychomotor and cognitive functioning 4.3 Healthy volunteers 12 4.4 Drug abusing populations 14 4.5 The effects of opiates in clinical populations 16 4.5.1 Non-cancer pain 16 4.5.2 Cancer pain 20 5. Summary of the effects on memory 23 6. Linking the effects of opiates on memory to current 23 understanding of normal memory 7. Gender differences in response to opiates 25 8. Clinical implications 27 9. Future Research 28 References 26 Part 2: Empirical paper 41 Abstract 42 Introduction 43 Method 54 Results 63 Discussion 75 References 90 Part 3: Critical Appraisal 98 1. Personal reflections on the research process 99 1.1 Thought processes and expectations 99 1.2 Practical issues 101 1.3 Personal gains 105 2. Critical appraisal of the research 106 2.1 Generalising to clinical populations 106 2.2 Tests used 108 2.3 Gender Differences 109 2.4 Relation to theoretical framework 109 2.5 Payment 110 3. Further research 110 4. Future directions 111 Referemces 112 Appendices Page Appendix A: Study protocol and explanation of joint working 113 Appendix B: Official letter of ethical approval 114 Appendix C: Advert for study 115 Appendix D: Consent form 116 Appendix E: Participant information sheet 117 Appendix F Somatic Effects Scale (SES) questionnaire 118 Appendix G: Drug Effects Scale (DES) questionnaire 119 List of Tables Page Table 1. Order and Timing of test administration 58 Table 2. Demographic information for the participants 63 Table 3. Mean (S.D.) scores for the cognitive and 64 psychomotor tests. Table 4. Mean scores (SD) for subjective Visual Analogue 70 Scale ratings from the Somatic Effects Scale (SES), the Mood Ratings Scale (MRS) and the Drug Effects Scale (DES) List of figures Page Figure 1. Male and Female mean (+S.E.) no. of digits recalled 65 on the Digit Span backwards Figure 2. Mean (+S.E.) proportion of pre-drug story units recalled 66 after delay compared with immediate recall (delay/immediate). Figure 3. Mean (+S.E.) number of story units recalled during 67 delayed prose recall. Figure 4. Mean (+S.E.) no. of source errors made on the Source 68 Memory test. Figure 5. Mean (+S.E.) VAS rating for hunger 71 Figure 6. Mean (+S.E.) VAS rating for Light Headedness 71 Figure 7. Mean (+S.E.) VAS rating for Pleasant Body Sensations 71 Figure 8. Mean (+S.E.) VAS rating for Dizziness 71 Figure 9. Mean (+S.E.) Sedation Score calculated from the Mood 72 Rating Scale Figure 10. Mean (+S.E.) VAS rating for feeling drug effect 73 Figure 11. Mean (+S.E.) VAS rating for wanting more /wanting less 73 Acknowledgements I would like to thank Val Curran for invaluable help and support throughout the process. Also thanks to James Holding and Brigitta Brandner, for medical advice and for arranging all the practicalities of working in the hospital. Thanks to Jason Wakeland-Smith and the rest of the pharmacy team at UCLH, to UCL graduate school for funding the research. To Lesilie, Rosa and Celia, for always being on hand for help and advice, and thanks Caroline for keeping spirits up. Finally, thanks to my parents for all their support. Part 1 Literature Review “How do opiates affect memory?” 1 Abstract Opiates have been commonly used for the management of pain for many years. Despite this, there is a surprising lack of research into the effects of opiates on cognition, with far more research having been carried out on other classes of psychotropic drugs. This paper will outline why it is important to understand the cognitive effects of opiates, in particular the short acting opiates morphine and oxycodone. It will review past research into the area to demonstrate the level of current understanding. The author is particularly interested in the results of a recent paper (Kamboj et al., 2005) that demonstrated an apparent retrograde memory impairment caused by morphine. As well as providing clinically relevant information about the cognitive effects of opiates, this finding also provides us with some theoretical insights into the normal workings of memory and has implications for future research. 2 1. Introduction The following review investigates both the importance of furthering our knowledge of the cognitive side effects of opiates and the current understanding of these effects. The bulk of the paper reviews studies that have investigated the cognitive effects of opiates in a variety of settings. The review will then attempt to synthesise the current knowledge of the effects of opiates on memory with current understanding of memory function. Finally, some recent articles relating to how weight and gender can mediate the effects of opiates are presented. Two databases were searched: PsychlNFO 1966 to April 2006 and MEDLINE 1966 to April 2006. The search parameters provided articles with any one of the following key words; opiate, opioid, morphine, oxycodone with any of these key words; memory, cognitive, cognition, amnesia. The abstracts from these articles were read by the author, studies using scientific method for assessing the cognitive effects of opiates were included. 2. Why is it important to understand the effects of opiates? 2.7. Clinical use of opiates Opiates are commonly used as analgesia in the treatments of both acute pain (following injury or surgical procedures) and persistent pain (including cancer-pain and chronic non-cancer pain). In the past there has been a reluctance to prescribe opiates, especially on an outpatient basis for chronic non-cancer pain, for three main reasons. Firstly there is concern that patients may suffer too much from the side effects, including sedation and cognitive impairment. Secondly, there are fears that patients may build up a tolerance to the drugs or may become addicted. Finally, there 3 is some concern that increased prescribing of these drugs on an outpatient basis would lead to higher rates of drug abuse in the general population due to the greater number of opiates available outside of clinical settings. It is estimated that in the UK, 2 - 6 million people have persistent severe non-cancer pain (British Pain Society, 2004), with an estimated 30 million adults in the USA (Joranson, Tyan, Gilson & Dahl, 2000) showing that in this clinical population alone there are a significant number of people who may be have a potential benefit or risk due to opiate use. Recent research has addressed some of these concerns, indicating that some of the reasons for the reluctance in prescribing may be unfounded. Whilst there is some evidence that patients may develop tolerance to opiates, the increase in dose needed to produce adequate analgesia is often associated with an increase in pain symptoms as illness progresses and it can be difficult to deduce whether higher doses needed are due to tolerance or increased pain (Houde, 1985). Fears that clinical opioid use for pain management may lead to drug addiction may be assuaged by evidence showing that the typical drug seeking behaviour demonstrated by addicts does not occur in patients after opioid prescription for childbirth, operations and myocardial infarctions (Gould et al., 1992) and addiction rates in general clinical populations taking opioids have been shown to be less than 1% (Melzack, 1992).