Campbell FA, Tramer NR, Carroll D, Reynolds DJM, Moore RA, McQuay HJ. BMJ 2001;323:1-6

Prepared by: : Dr. Sharon Watanabe

Received during: Journal Club on the Tertiary Palliative Care Unit

Abstract:

Objective: To establish whether cannabis is an effective and safe treatment option in the management of pain.
Design: Systematic review of randomised controlled trials.
Data sources: Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searchers.
Study selection: Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford source.
Data extraction: Independent data extraction; discrepancies resolved by consensus.
Data synthesis: 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common.
Conclusion: Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable. In acute postoperative pain they should not be used. Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomised controlled studies are needed.

Comments:

Strengths/uniqueness: This is the first systematic review of randomized controlled trials of cannabinoids for pain management. A focused clinical question was addressed. Selection criteria were appropriate. The literature search was comprehensive. Validity of individual studies was appraised. Independent assessments were performed by the researchers.

Weaknesses: The heterogeneity of the individual studies precluded quantitative meta-analysis. Most trials evaluated cannabinoids administered as single doses only. No studies assessed smoked cannabis. An n-of-1 study demonstrating benefit for neuropathic pain and spasticity in a single patient with multiple sclerosis appears to have been given undue emphasis in the discussion.

Relevance to Palliative Care: This review suggests that cannabinoids confer limited analgesic benefit with significant central nervous system adverse effects. The routine use of cannabinoids in palliative patients for treatment of pain is therefore not supported by the current literature. Research is underway to develop cannabinoids with greater therapeutic effects and less toxicity.

Management of Pain and Pain-Related Symptoms in Hospitalized Veterans with Cancer.
McMillan SC, Tittle M, Hagan S, Laughlin. J. Cancer Nursing 2000; 23(5):327-336.

Prepared by: Dr. Robin Fainsinger

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

Abstract:

Unrelieved pain continues to be a problem among hospitalized patients with cancer. The purpose of this study was to evaluate pain management outcomes in a group of veterans with cancer receiving inpatient care. The sample consisted of 90 veterans with cancer hospitalized in one of two large veteran's medical centers in the southeastern United States. Daily pain was assessed by administering the visual analog scale (VAS) for pain three times in a 24-hour period and averaging these three scores. The Brief Pain Inventory (BPI) and Constipation Assessment Scale (CAS) were administered once. The charts were audited using the Chart Audit for Pain (CAP). The sample was predominantly male (93.3%) and white (82.8%). The length of time since diagnosis ranged from newly diagnosed during this hospitalization to 16 years. Average daily pain was 32.9 on the VAS and 4 on the PBI. However, approximately one-fourth of the patients reported average daily pain above the midpoint (VAS > 50), and some patients reported average daily pain to be as high as 98. Fewer than half of charts (42%) showed evidence that a pain rating scale were used. Other assessment data also were very limited. Patients reported that pain interfered with all activities on the BPI, with highest interference scores for walking and sleep (mean, 5.5). Although 80% of the patients reported some problem with constipation, the chart audit indicated that this was recorded in only 11 patient records. No patient records indicated a problem with sedation. The findings indicate that limited attempts were made to manage pain using nonpharmacologic methods. In addition, only one of the nine charts reporting these attempts showed evidence that results from the attempt were evaluated. It may be concluded that pain management continues to be less than ideal in these veterans' hospitals. Study results indicate that nurses are not documenting careful assessment of pain, not documenting evaluation of approaches to pain management, and not attending to the constipation that is inevitable when opioids are administered. Continued emphasis on nursing education related to pain management is needed. Future research should be undertaken to evaluate these outcomes.

Comments:

Strengths/uniqueness: A well described approach to a comprehensive assessment of pain in cancer patients in an acute care setting. A useful model for palliative care consult teams in similar settings to consider using to audit pain assessment.

Weaknesses: The VAS and BPI (with the exception of the interference subscale) are a unidimensional pain assessment. The authors imply that increased pharmacological management will resolve all of the uncontrolled pain experienced by patients in this study. Given the complexity and multi-dimensional aspects of expression of total suffering in some patients' complaint of pain, this is over simplistic.

Relevance to Palliative Care: This report certainly indicates the ongoing need to better assess, document, educate and manage pain in the acute care setting. The statement that "the desired outcome of a pain free state for every patient was not being met" should be interpreted with caution to avoid unrealistic expectations of pain management and/or palliative care consulting teams.

A cross-national study of the course of persistent pain in primary care.
Gureje O, Simon GE, Von Korff M. Pain 2001; 92:195-200.

Prepared by: Dr. Robin Fainsinger

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

Abstract:

Data from the World Health Organization's study of psychological problems in general health care were used to examine the course of persistent pain syndromes among primary care patients. Across 15 sites in 14 countries, 3197 randomly selected primary care patients completed baseline and 12-month follow-up assessments of pain, other somatic symptoms, and anxiety and depressive disorders (the Composite International Diagnostic Interview), and an assessment of occupational role disability (the Social Disability Schedule). Of patients with a persistent pain condition at baseline, 49% had not recovered 12 months later. The probability of non-recovery varied significantly across study centers and was significantly associated with the number of pain sites at baseline. After adjustment for age, sex, and study centre, baseline anxiety or depressive disorder did not predict non-recovery of persistent pain. Among those without a persistent pain disorder at baseline, the rate of onset was 8.8% with a significant variability in risk across centres. The baseline characteristics predicting the onset of persistent pain disorder were psychological disorder, poor self-rated health, and occupational role disability. A persistent pain disorder at baseline predicted the onset of a psychological disorder to the same degree that a baseline psychological disorder predicted the subsequent onset of persistent pain. Persistent pain conditions are common among primary care patients, and the probability of resolution over 12 months is approximately 50%. We found a strong and symmetrical relationship between persistent pain and psychological disorder. Impairment of daily activities appears to be a central component of that relationship.

Comments:

Strengths/uniqueness: Multi-site, multi-cultural studies are time-consuming and difficult to implement, making this 14-country pain study a commendable effort.

Weaknesses: It would have been interesting to read comments on clinical implications of the connection between persistent pain, pain onset and psychological and disability disorders.

Relevance to Palliative Care: The study population is primary care patients and not specifically cancer patients, but this study highlights the need to consider disability/psychological impact on pain problems, and ensure psychological and rehabilitation support are not forgotten in our enthusiasm to use pharmacological management.

Prevalence and management of cancer pain in South Africa.

Beck SL, Falkson G. Pain 2001; 94(1):75-84.

Prepared by: : Dr. Robin Fainsinger

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

Abstract:

Inadequate relief from cancer pain is an international health problem. The aim of this study was to document the prevalence and patterns of cancer pain management in the Republic of South Africa. The first phase of this study consisted of screening 263 patients to document the prevalence of cancer pain in varying settings. A total of 94 patients were experiencing cancer-related pain; this comprised 35.7% of the sample. Inpatients had a higher prevalence than outpatients, which is likely due to the fact that these patients are more acutely ill. Blacks (56.1%) had a higher prevalence of pain than whites (29.4%, P < 0.005); this difference was most pronounced in the outpatient setting. Phase 2 consisted of asking 426 patients with cancer pain from different settings to complete a questionnaire that included the brief pain inventory and was designed to learn about their pain and how it was managed. Nearly one-third of the entire sample experienced 'worst pain' of severe intensity. There was little difference between the public and private cancer care centers. The lowest percentage of patients with severe 'worst pain' was in the hospice setting, but even in this group about one-fourth of the patients had peak pain that was severe. Of non-whites combined, 81% experienced 'worst pain' of moderate to severe intensity as compared to 65% of whites (P < 0.001). Only 21% of patients reported that they had achieved 100% pain relief. Patients experienced interference in general activity, mood, walking, working, relations with others, sleeping, and enjoyment of life related to their pain. 30.5% of the entire sample had a negative score on the pain management index, a comparison of the most potent analgesic used by a patient relative to their worst pain. Of this group, 58.1% were experiencing severe 'worst pain'. Unrelieved cancer pain is a significant problem. Government and non-government leaders, educators, and practitioners must collaborate to address the barriers to effective pain management and to implement improvements in education, health policy, and health care delivery.

Comments:

Strengths/uniqueness:This report is a useful contribution to document the extent of the existing problem of cancer pain management in a country with a unique mix of first and third world patients and health care facilities.

Weaknesses: The methodology does not appear to have been designed to truly represent the demographics of the South African population. The 'white' population, the urban areas, and wealthier people able to access private facilities are likely over represented.

Relevance to Palliative Care: This report does present a challenge to all countries to do similar work to assess prevalence and adequacy of cancer pain management. Countries with significant advances in palliative care such as Canada would do well to document whether our results are any better given our advantages in health care resources.

"Burst" ketamine for refractory cancer pain: An open-label audit of 39 patients.
Jackson K, Ashby M, Martin P, Pisasale M, Brumley D, Hayes B. J Pain Symptom Manage 2001; 22(4):834-842.

Prepared by: Dr. Robin Fainsinger

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

Abstract:

The results of a novel approach to the use of ketamine in refractory cancer pain are reported. In this prospective, multicentre, unblinded, open-label audit, 39 patients (with a total of 43 pains) received a short duration (3 to 5 days) ketamine infusion. The initial dose of 100 mg/24 hr was escalated if required to 300 mg/34 hr and then to a maximum dose of 500 mg/24 hr. The overall response rate was 29/43 (67%). Analysis of results according to pain mechanisms showed that 15/17 somatic and 14/23 neuropathic pains responded. In 5 patients who appeared to respond, it is possible that another concurrent intervention may have contributed in whole or part for the pain relief observed. After cessation of ketamine, 24/29 maintined good pain control, with a maximum documented duration of eight weeks. However 5 of the initial 29 responders experienced a recurrence of pain within 24 hours, and ketamine was recommenced. Of these, 2 underwent another intervention for pain control while 3 continued on ketamine until their deaths between two and four weeks later. Twelve patients reported adverse psychomimetic effects, with the incidence rising with increasing dose. Four of these were non-responders and the ketamine was stopped. Eight were responders, and in 3 the adverse effects were rendered acceptable with dose reduction; the other 5 rejected a dose reduction. The results reported suggest the need for further investigation of the place of ketamine in cancer pain management.

Comments:

Strengths/uniqueness:This report is improved by the prospective study design, as well as the clear description of outcome measures to define response to the ketamine protocol.

Weaknesses: As noted by the authors, it is not possible to exclude placebo effect and observer bias. A major weakness is the lack of discussion on the use of methadone in refractory pain management, an opioid that was clearly underused in this patient population.

Relevance to Palliative Care: The success of the ketamine protocol in this patient population may well justify consideration of this approach in other settings. An open randomized study of refractory pain syndromes using ketamine or methadone might be interesting.

Assessment of pain control in cancer patients during the last week of life: Comparison of health centre wards and a hospice.
Hinkka H, Kosunen E, Kellokumpu-Lehtinen P, Lammi Ulla-Kaija. Support Care Cancer 2001; 9:428-434.

Prepared by: Dr. Robin Fainsinger

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

Abstract:

The aim of this prospective study was to assess the quality of cancer pain control during the last week of life in two different types of units for terminal cancer patients in Finland: on health centre wards (N = 20) and in a hospice (N = 30). Pain scores (VAS), defined daily doses (DDD), routes of administration and costs of pain medication were analysed for each patient. On the 7th-last day before death and during the very last day of life (24 h), respectively, the following results were seen: proportions of patients using strong opioids 64% and 84%, mean equivalent parenteral morphine doses of strong opioids 42 mg and 57 mg, mean pain scores (VAS 0-10) 3.11 and 3.05, mean daily cost of pain medication 2.22 and 2.90 euros. Pain control was thus found to be good with low costs. On the 7th day before death strong opioids were used for a greater proportion of patients on the health centre wards. Differences were also seen in the routes of administration used for strong opioids. Weak opioids were used more in the hospice and NSAIDs, more on the health centre wards. However, no differences were found either in the mean doses of strong opioids or in the quality or the costs of pain control between the health centre wards and the hospice.

Comments:

Strengths/uniqueness:This study demonstrates the importance of systematic pain and symptom measurement. As a result the report could describe pain control information rather than relying on opioid use and vague chart descriptions.

Weaknesses: This report describes the Visual Analogue Scale as being patient or staff assisted reporting. However it is predictable that many of these patients would have been unable to report pain level in any meaningful way, particularly in the last 24 hours before death. This point does not appear to be recognized by the study's authors. A further major weakness is the categorization of diagnosis as cancer pain, without any recognition of poor prognostic factors that can influence pain intensity and outcome measures.

Relevance to Palliative Care: The study is reassuring in demonstrating an excellent prevalence of reasonable analgesic management in both specialist and general practitioner settings. However it also inadvertently highlights the need for reports to be able to use an internationally recognized classification system for cancer pain. This would allow a more meaningful comparison of research results.

Improving pain management in long-term care facilities

Weissman, DE, Griffie J, Muchka S, Matson S. J of Palliative Medicine 2001; 4(4):567-573

Prepared by: : Dr. Robin Fainsinger

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

Abstract:

Improving pain management in long-term care facilities has several unique barriers in comparison to the acute hospital setting. To address these barriers the Medical College of Wisconsin in Palliative Care Program began a project in 1996, initially working with 87 long-term care facilities, to improve pain management practices through a series of educational and quality improvement steps. This article will review the overall structure, results, strengths and weaknesses of this approach to improving pain management in this important site of clinical care. This article was excerpted from a thematic issue, "Promoting Better Pain management in Long-Term Care Facilities", Volume 3, Number 1, 2001 of the online journal Innovations in End-of-Life Care at < www.edc.org/lastacts/>.

Comments:

Strengths/uniqueness: The report provides a good outline of an approach used by an experienced team to educate staff in long-term care facilities, and improve pain management for all residents irrespective of the diagnosis.

Weaknesses: Physicians appear to have been excluded in this educational approach, although they are expected to approve recommendations made to them by nurses. Although target indicators were used and some results reported to demonstrate markers of success, these indicators did not necessarily prove improvement in actual pain management.

Relevance to Palliative Care: There is a challenge contained in this report to all long-term care facilities to assess their pain management practices, and consider an evaluation and process to improve existing circumstances.

Sensory and affective dimensions of advanced cancer pain. Sela R, Bruera E, Conner-Spady B, Cumming C, Walker C. Psycho-Oncology 2002; 11:23-34 Downloadable PDF File

Prepared by: Dr. Robin Fainsinger

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

Abstract:

The present study was designed to explore the extent to which advanced cancer pain is explicable in terms of both physical pain intensity and affect. Most notably, it expanded on previous findings by more clearly elucidating the relationship between several discrete emotional states and the total experience of cancer pain. One hundred and eleven patients with cancer pain attending a Pain and Symptom Control Clinic were studied. Visual Analogue Scales (VAS) were used to quantify overall pain intensity and the accompanying affect. Then, correlations were calculated to evaluate the relationships both between and within these two variables. Overall, the participants rated both the pain intensity and the negative affect associated with that pain as high. Of the examined affective components of pain, frustration and exhaustion were found to be the most significant. In addition, some gender differences were identified in terms of frustration, anger, fear, exhaustion, helplessness, and hopelessness.

Comments:

Strengths/uniqueness:
This report underlines the importance of multi-dimensional pain assessments in cancer patients.

Weaknesses:
The results are from a study group of highly selected problematic cancer patients referred to a specialist pain and symptom control clinic. Correlation with a multi-dimensional classification system such as the Edmonton Staging System would have been useful to better understand underlying poor prognostic factors in this patient population.

Relevance to Palliative Care:
This study underlines the need for carefully designed future pain studies to clarify whether the issues of patient affect demonstrated here contribute significantly to the pain perception and expression of the uncontrolled pain results in the affective problems noted.

Effects of emotion on pain reports, tolerance and physiology. Carter LE, McNeil DW, Vowles KE, et al. Pain Research & Management 2002; 7(1):21-30 Downloadable PDF File

Prepared by: Dr. Robin Fainsinger

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

Abstract:

The effects of specific emotional states on a laboratory pain task were tested by examining the behavioural, verbal and psychophysiological responses of 80 student volunteers (50% female). Participants were assigned to one of four Velten-style emotion-induction conditions (i.e., anxiety, depression, elation or neutral). The sexes of experimenters were counterbalanced. Overt escape behaviour (i.e. pain tolerance), pain threshold and severity ratings, verbal reports of emotion and physiological measures (i.e., electrocardiogram, corrugator and trapezium electromyogram) were recorded. A pressure pain task was given before and after the emotion induction. As predicted, those who participated in the anxiety or depression condition showed reduced pain tolerance after induction of these negative emotions; pain severity ratings became most pronounced in the depression condition. A pattern of participant and experimenter sex effects, as well as trials effects, was seen in the physiological data. The influence of negative affective states (i.e., anxiety and depression) on acute pain are discussed along with the unique contributions of behavioural, verbal and physiological response systems in understanding the interactions of pain and emotions.

Comments:

Strengths/uniqueness:
This is a detailed, well-described report of reproducible laboratory research on healthy volunteers subjected to a controlled pain experience and emotional manipulation.

Weaknesses:
The generalizability of findings to the chronic pain and emotions of palliative care patients has to be viewed with caution. Consideration of cultural differences is a further limiting factor.

Relevance to Palliative Care:
This is further evidence to demand consideration of how psychosocial issues and coping mechanisms of palliative patients affects pain tolerance and expression. Carefully designed trials of psychological assessment and counseling in palliative patients could provide important information to suggest ways to supplement the limitations of pain control with pharmacological management alone.

Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Moryl N, Santiago-Palma J, Kornick C, Derby S, Fischberg D, Payne R, Manfredi PL. Pain 2002; 96:325-328.Downloadable PDF File

Prepared by: Dr. Robin Fainsinger

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

Abstract:

The successful use of methadone in cancer pain has been supported by numerous case reports and clinical studies. Methadone is usually used as a second or third line opioid medication. As the use of methadone increases we are facing the challenge of converting methadone to other opioids as part of sequential opioid trials. Data on the equianalgesic ratios for the substitution of other opioids for methadone are lacking. We present prospective data on 13 consecutive rotations from methadone to a different opioid. The opioid rotation was followed by escalation of pain and/or severe dysphoria, not controlled by a rapid increase in the dose of the second opioid, in 12 of the 13 patients. Only one patient was successfully maintained on the second opioid after the discontinuation of methadone, while 12 patients required a switch back to methadone. We conclude that opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria. These symptoms may not improve despite upward titration of the second opioid. A uniformly accepted conversion ratio for substituting methadone with another opioid is currently not available. More data on the rotation from methadone to other opioids are needed.

Comments:

Strengths/uniqueness:
This report provides a well described case series of clinically useful information that is of relevance to all programs advocating and using methadone for the management of cancer pain.

Weaknesses:
The report does not present a solution to this problematic clinical situation, and findings may be limited to patients with some opioid analgesic resistance.

Relevance to Palliative Care:
The findings highlight the need for caution when switching from methadone to an alternative opioid, and the risk of precipitating an increasing pain crisis. The tapered approach as suggested by the authors is deserving of further exploration.

Rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion.Mercadante S, Villari P, Ferrera P, Casuccio A, Fulfaro F. Cancer 2002;95:203-208.Downloadable PDF File

Prepared by: Dr. Sharon Watanabe

Received during: Journal Club on the Tertiary Palliative Care Unit

Abstract:
BACKGROUND: Cancer pain emergencies presenting with severe excruciating pain require a rapid application of powerful analgesic strategies. The aim of the current study was to evaluate a method of rapid titration with intravenous morphine to achieve relief of cancer pain of severe intensity.
METHODS: Forty-nine consecutive patients admitted to a Pain Relief and Palliative Care Unit for severe and prolonged pain were enrolled in the study. Pain was evaluated on a numeric scale of 0-10 (0 indicated no pain and 10 indicated excruciating pain). After the initial assessment (T0), an intravenous line was inserted and boluses of morphine (2 mg every 2 minutes) were given until the initial signs of significant analgesia were detected or severe adverse effects occurred (T1). A continuous reassessment was warranted and the effective total dose administrated intravenously was assumed to last approximately 4 hours and was calculated for 24 hours. The dose immediately was converted to oral morphine (a 1:3 ratio for low doses and a 1:2 ratio for high doses).
RESULTS: Data from 45 patients was analyzed. A significant decrease in pain intensity was achieved in a mean of 9.7 minutes (95% confidence interval [95% CI], 7.4-12.1 minutes), using a mean dose of intravenous morphine of 8.5 mg (95% CI, 6.5-10.5 mg). The doses administered rapidly were converted to oral morphine and pain control was maintained until the patient's discharge, which occurred in a mean of 4.6 days (95% CI, 4.1-5.2 days). The incidence of adverse effects was minimal.
CONCLUSIONS: The results of the current study demonstrate that cancer pain emergencies can be treated rapidly in the majority of cancer patients with an acceptable level of adverse effects. Intravenous administration of morphine requires initial close supervision and continuity of medical and nursing care.

Comments:

Strengths/uniqueness: The study's strengths include its prospective design, the standardized treatment protocol and the systematic assessment of pain intensity and adverse effects of morphine.

Weaknesses: Given the uncontrolled and unblinded nature of the study, the subjective symptom ratings are open to bias. More detailed characterization of the patient population (baseline opioid doses, cognition, psychological state, coping history) would have been helpful for interpretation of results.

Relevance to Palliative Care: This study suggests that intravenous morphine titration may achieve pain control in a rapid and safe manner, in patients with severe cancer pain who are opioid-naïve or on low opioid doses and who are admitted to an inpatient setting. However, it is debatable whether this approach is advantageous compared to oral titration in an outpatient setting. The mean oral morphine dose on the day after the intravenous titration was 104 mg/day, which probably could have also been achieved with short-acting oral morphine every four hours plus breakthrough doses every hour as needed. Although pain control may be achieved in minutes with the intravenous route as opposed to hours with the oral route, the significance of the time difference is unclear, given that these patients were said to have been in severe pain for days already. Oral titration may avoid the need to hospitalize the patient; however, its success depends on frequent monitoring by the physician for dose adjustments.

Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival. Downloadable PDF File

Smith TJ, Staats PS, Deer T, et al. J of Clinical Oncology 2002; 29(19):4040-4049.

Prepared by: Dr. Robin Fainsinger

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

Abstract:

Purpose: Implantable intrathecal drug delivery systems (IDDSs) have been used
to manage refractory cancer pain, but there are no randomized clinical trial (RCT) data comparing them with comprehensive medical management (CMM).
Patients and Methods: We enrolled 202 patients on a RCT of CMM versus IDDS plus CMM. Entry criteria included unrelieved pain (visual analog scale [VAS] pain scores = 5 on a 0 to 10 scale). Clinical success was defined as = 20% reduction in VAS scores, or equal scores with = 20% reduction in toxicity. The main outcome measure was pain control combined with change of toxicity, as measured by the National Cancer Institute Common Toxicity Criteria, 4 weeks after randomization.
Results: Sixty of 71 IDDS patients (84.5%) achieved clinical success compared with 51 of 72 CMM patients (70.8%, P = .05). IDDS patients more often achieved = 20% reduction in both pain VAS and toxicity (57.7% [41 of 71] vs 37.5% [27 of 72], P = .02). The mean CMM VAS score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the scores fell from 7.57 to 3.67 (52% reduction, P = .055). The mean CMM toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group, the toxicity scores fell from 7.22 to 3.59 (50% reduction, P = .004). The IDDS group had significant reductions in fatigue and depressed level of consciousness (P < .05). IDDS patients had improved survival, with 53.9% alive at 6 months compared with 37.2% of the CMM group (P = .06).
Conclusion: IDDSs improved clinical success in pain control, reduced pain, significantly relieved common drug toxicities, and improved survival in patients with refractory cancer pain.

Comments:

Strengths/uniqueness:

This is an original study with an interesting and well-described design that compares spinal opioids to best medical management.

Weaknesses:

The unblinded study design is a weakness, but it would be very difficult to blind patients given the nature of IDDS.

Relevance to Palliative Care:

This data does suggest that IDDS delivery may offer benefit for some cancer patients, however more research is required to determine which patient subset would be mostly likely to benefit.

"Burst" Ketamine for Refractory Cancer Pain: An Open-Label Audit of 39 Patients Downloadable PDF File

Jackson K, Ashby M, Martin P, et al. J of Pain & Symptom Manage 2001; 22:834-842.

Prepared by: Lori Stead, M.D.

Received during: Journal Club (19th October 2006)
Tertiary Palliative Care Unit, Grey Nuns Hospital

Abstract

The results of a novel approach to the use of ketamine in refractory cancer pain are reported. In this prospective, multicenter, unblended, open-label audit, 39 patients (with a total of 43 pains) received a short duration (3 to 5 days) ketamine infusion. The initial dose of 100 mg / 24 hour was escalated if required to 300 mg / 24 hour and then to a maximum dose of 500 mg / 24 hour. The overall response rate was 29/43 (67%). Analysis of results according to pain mechanisms showed that 15/17 somatic and 14/23 neuropathic pains responded. In 5 patients who appeared to respond, it is possible that another concurrent intervention may have contributed in whole or part for the pain relief observed. After cessation of ketamine, 24/29 maintained good pain control, with a maximum documented duration of eight weeks. However, 5 of the initial 29 responders experienced a recurrence of pain within 24 hours, and ketamine was recommenced. Of these, 2 underwent another intervention for pain control while 3 continued on ketamine until their deaths between two and four weeks later. Twelve patients reported adverse psychomimetic effects, with the incidence rising with increasing dose. Four of these were non-responders and the ketamine was stopped. Eight were responders, and in 3 the adverse effects were rendered acceptable with dose reduction; the other 5 rejected a dose reduction. The results reported suggest the need for further investigation of the place of ketamine in cancer pain management.

Comments

Strengths/uniqueness:

This patient population was comparable to other inpatient palliative care units with respect to age, disease, functional status and prognosis. Adds to the limited data available on ketamine use in palliative care and provides a methodology for use. Good response rate (67%) in patients with little in the way of other options. Duration of response generally good.

Weaknesses:

Not a randomized or blinded study. No real statistical analysis. Small study of 39 patients.

Relevance to Palliative Care:

We should consider wider use of ketamine in appropriate patients.

Prospective Audit of Short-Term Concurrent Ketamine, Opioid and Anti-inflammatory ('triple-agent') Therapy for Episodes of Acute on Chronic Pain. Downloadable PDF File

Good P, Tullio F, Jackson, et al. Internal Medicine Journal 2005; 35:39-44.

Prepared by: Dr. Scott Loree

Received during: Journal Club (31st October, 2006)
Tertiary Palliative Care Unit, Grey Nuns Hospital

Abstract

Aim: This prospective audit was undertaken in order to document the analgesic response and adverse effects of concurrent short-term ('burst') triple-agent analgesic (ketamine, an opioid and an anti-inflammatory agent - either steroidal or non-steroidal) administration, for episodes of acute on chronic pain. The clinical hypothesis in this study is that better pain control may be obtained by simultaneous multiple target receptor blockade. Method: The response of 18 patients is reported. The pain and analgesic requirement data for the 24 h before starting triple-agent therapy were compared with the last 24 h on the triple-agent therapy. Patients were then classified as responders or non-responders. Results: According to stringent clinical criteria, 12 out of the 18 patients were classified as responders. The response rate was highest for somatic pain (7/9) and appeared to decrease with duration of prior uncontrolled pain. Only four out of the 18 patients reported adverse effects and all of these were minor. Conclusions: The results suggest that this 'burst' triple-agent approach is safe and effective in an inpatient palliative care population during episodes of poorly controlled acute on chronic pain, and warrants further investigation to ascertain whether it gives superior results compared to the 'gold-standard' WHO ladder approach.

Comments

Strengths/uniqueness:
This is a prospective six month 18 patient case series of palliative inpatients with a variety of terminal cancers suffering from pain with "unstable pain control", which the authors define as moderate to severe 5-10/10 pain. The patients all had poor response to prior attempts at pain control, and all were suffering most from neuropathic and incident pain. The study attempts some stratification of patients with respect to pain type, and provides a good account of complication rates and measures of treatment success with reductions in MEDD and improved VAS pain scores. Some patients received Ketorolac as the anti-inflammatory component of their therapy, and some received dexamethasone.

Weaknesses:
This is a small case series, and although prospective, it is not blinded or randomized in any way. This is, however, a difficult research question to randomize. The generalizability suffers because there is little measure of palliative performance before the treatment was begun, and there is no sense of patients' tumor burden at the start of the study. The authors report the median parenteral MEDD before starting the protocol as 66 mg/24h, which is quite moderate in terms of the experience in Edmonton.

Relevance to Palliative Care:
Controlling neuropathic and incident pain control is often challenging in palliative medicine practice, and is most distressing for both the physician and the patient. Ketamine burst protocols have been used for further NMDA blockade, reduction in total opioid dose, and re-setting of central sensitization. This study, although flawed, provides some further evidence of it's usefulness in treating difficult to treat pain syndromes.

Successful use of ketamine for intractable cancer pain. Downloadable PDF File

Lossignol DA, Obiols-Portis M, Body JJ. Support Care Cancer 2005; 13:188-93

Prepared by: Prabhu Sonpar

Received during: Journal Rounds on the Tertiary Palliative Care Unit, Nov. 9, 2006

Abstract
Background: Despite medical awareness, intractable pain is a serious problem in cancer and occurs in up to 2% of advanced cancer patients. However, few data are available concerning the optimal treatment of such patients. The emergence of intractable pain may notably be due to the activation of N-methyl-D-aspartate (NMDA) receptors located in the central nervous system. NMDA antagonists might thus be an interesting approach in such pain syndromes. Patients and methods: Twelve patients with intractable cancer pain received a test dose of 5-10 mg of ketamine, a strong NMDA antagonist, in order to determine their response and tolerance to the drug. Continuous intravenous infusions of ketamine associated with morphine were then administered. Main results: The acute test dose was successful in all cases (VAS<3/10 after 5 min). The prolonged use of ketamine allowed us to reduce the total daily dose of morphine required (range: 200-1,200 mg) by 50% and allowed eight patients to go home with a portable pump with morphine and ketamine during a relatively long period of time (range: 7-350 days, median: 58 days). Side effects were moderate (dizziness) and they were limited to the test phase. Conclusion: Our data suggest the importance of NMDA receptors in the genesis of chronic cancer pain and indicate that NMDA antagonists should be further studied for the management of cancer pain and, in particular, intractable pain.

Comments

Strengths/uniqueness:
Study done for intractable pain on different tumor types and pains. The aim was pain relief. 100% patients followed until patients died.

Weaknesses:
Small study of 12 patients. Followed for 7-64 days in majority (only 3 patients followed for more than 100 days). Claim 50% reduction in morphine not reflected in Table 3. Long term side effects not well documented.
Ketamine was mixed with morphine and no comparisons made, no placebo. Lack of acknowledgement of methadone as medication for intractable pain.

Relevance to Palliative Care:
Intractable pain remains a challenge in palliative care. A larger, longer trial comparing various pain management medications would be helpful.

Pain Management in Hospitalized Cancer Patients: A Systematic Review. Downloadable PDF File

Goldberg GR, Morrison RS. J Clin Oncol 2007; 25:1792-1801

Prepared by: Sharon Watanabe

Received during: Journal Club at CCI

ABSTRACT
Purpose: To assist cancer centers in improving pain management, we conducted a systematic review of institutional interventions designed to improve the assessment and treatment of pain in hospitalized cancer patients.
Methods: We performed a MEDLINE search for all English-language articles published from January 1966 through February 2006 using the medical subject headings terms of pain or pain measurement and outcome assessment (health care) or quality assurance (health care). Selected bibliographies were also searched. Studies were reviewed if they included clinical interventions directed at improving the treatment of cancer pain across an institution or nursing unit. Meta-analyses and randomized controlled trials or other controlled studies were included where possible. If no such trials were identified, then the best evidence available from studies with other designs was included.
Results: Five interventions were identified. These interventions included professional and patient education, instituting regular pain assessment (pain as a vital sign), audit of pain results and feedback to clinical staff, computerized decisional support systems, and specialist-level pain consultation services. Most studies were small in size and used quasiexperimental pre-post test designs. Successes were reported in increasing patient satisfaction, increasing documentation of pain intensity, and improving nurses' knowledge and attitudes. No study reported successful interventions that consistently improved patients' pain severity.
Conclusion: Although professional knowledge and attitudes about pain and nursing pain assessment rates have been shown to be improvable, no systematic, hospital-wide intervention has yet to be associated with improvement in pain severity. Future research on the development of new interventions, perhaps targeted specifically at physicians, is urgently needed.

COMMENTS

Strengths/uniqueness: This is the first systematic review of studies of strategies to improve pain control in hospitalized cancer patients.

Weaknesses: Only a single database (Medline) was searched. The authors acknowledge that the search was limited to English-language papers, and that no attempt was made to identify unpublished studies. There was no formal quality assessment of identified studies, although quality was described informally.

Relevance to Palliative Care: Although pain management for hospitalized cancer patients has been documented to be suboptimal, existing evidence does not provide clear guidance on how to improve the situation. This review highlights the need for well-designed studies. Also, in order for results to be interpretable, it would be important to describe the pain syndromes in the population under study. In the meantime, evidence from one meta-analysis supports the role palliative care consultation services in improving pain outcomes; however, as it would not be feasible for such teams to see every hospitalized cancer patient, additional measures would need to be in place.