Appendix 1. Assessment of Scientific Evidence and Consultant Opinion
The scientific assessment of these guidelines was based on the following statements or evidence linkages. These linkages representdirectional hypotheses about relationships between cancer pain, symptom management, and clinical outcomes.
1. Comprehensive evaluation and assessment of pain (i.e., history, physical examination, laboratory evaluation)
improve analgesia, reduce adverse effects of pain therapy, and improve quality of life.
2. Longitudinal monitoring of pain (e.g., patient self-report, rating scales, and frequency of pain ratings)
improves analgesia, reduces adverse effects of pain therapy, and improves quality of life.
Involvement of specialists in multiple disciplines improves analgesia, reduces adverse effects of pain therapy,
i.e., systemic analgesia: oral medications administered by application of the
WHO pain ladder, rectal and transdermal analgesia, subcutaneous drug delivery, and intravenous drugdelivery) improve analgesia, reduce adverse effects of pain therapy, and improve quality of life. i.e., neuraxial drug delivery (epidural, subarachnoid, intraventricular), neural
blockade (diagnostic blockade, neural blockade for pain management), and neuroablation (chemical, thermal,and surgical neurolysis)) improve analgesia, reduce adverse effects of pain therapy, and improve quality oflife.
Management of cancer-related symptoms, side effects of cancer treatment, and adverse effects from pain
therapy (e.g., use of antiemetics and laxatives) improves analgesia, reduces adverse effects of pain therapy,and improves quality of life.
Psychosocial interventions for pain management and interventions to treat psychosocial consequences from
cancer pain and pain management improve analgesia, reduce adverse effects of pain therapy, and improvequality of life.
Home parenteral therapy improves analgesia, reduces adverse effects of pain therapy, and improves quality
End-of-life care improves analgesia, reduces adverse effects of pain therapy, and improves quality of life.
Special features of pediatric cancer pain management (
i.e., age-appropriate assessments and dosage levels,
interventions to alleviate fears and anxieties about pain therapy, less invasive routes of pharmacologicadministration) improve analgesia, reduce adverse effects of pain therapy, and improve quality of life.
Scientific evidence was derived from aggregated research literature with metaanalyses when appropriate, surveys, openpresentations, and other consensus-oriented activities. For purposes of literature aggregation, potentially relevant clinical studieswere identified via electronic and manual searches of the literature. The electronic search covered a 30-yr period from 1966 through1995. The manual search covered a 48-yr period from 1948 through 1995. More than 3,000 citations were identified initially, yielding953 non-overlapping articles that addressed topics related to the 10 evidence linkages. After review of the articles, 603 studies did notprovide direct evidence and were subsequently eliminated, yielding 350 articles containing direct evidence. Journals (n = 116)represented by the 350 articles included the following disciplines: anesthesiology, 205; oncology, 36; internal medicine, 3; neurology,4; neurosurgery, 34; nursing, 8; palliative care, 27; pediatrics, 6; pharmacology, 9; psychology, 14; and radiology, 4.
A directional result for each study was determined initially by classifying the outcome as either supporting a linkage, refuting a linkage,or neutral. The results were summarized to obtain a directional assessment of support for each linkage. The literature relating tolinkages 3 (involvement of specialists from multiple disciplines), 5a (neuraxial, i.e., epidural and subarachnoid drug delivery), 6(management of symptoms or adverse effects), and 9 (end-of-life care) contained enough studies with well defined experimentaldesigns and statistical information to conduct formal metaanalyses.
The following terms were used in the guidelines to express the strength of the evidence relating to various interventions and theirassociated outcomes: (1) insufficient data: There is insufficient published data to provide an indication of the relationship betweenintervention and outcome; (2) suggestive data: There is qualitative evidence in the form of case reports or descriptive studies, butthere is insufficient quantitative evidence to establish a statistical relationship between intervention and outcome; (3) supportive data:Quantitative data indicate a significant relationship between intervention and outcome (P < 0.01), and qualitative data are suggestive.
Combined probability tests were applied to continuous data, and an odds-ratio procedure was applied to dichotomous study results. Two combined probability tests were employed as follows: (1) Fisher's combined test, producing chi-square values based onlogarithmic transformations of the reported P values from the independent studies, and (2) the Stouffer combined test, providingrepresentation of the studies by weighting each of the standard normal deviates by the size of the sample. A procedure based on theMantel-Haenszel method for combining study results using 2 x 2 tables was used when sufficient outcome frequency information wasavailable. An acceptable significance level was set at P < 0.01 (one-tailed), and effect-size estimates were calculated. Interobserveragreement was established through assessment of interrater reliability testing. Tests for heterogeneity of the independent sampleswere conducted to assure consistency among the study results. To control for potential publishing bias, a "fail-safe n" value was
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calculated for each combined probability test. No search for unpublished studies was conducted, and no reliability tests for locatingresearch results were done.
. Significance levels from the weighted Stouffer combined test forclinical efficacy were significant for linkages 3 (multiple disciplines) and 5a (neuraxial drug delivery). The weighted Stouffer test forlinkage 9 (end-of-life care) was not significant. Weighted effect size estimates ranged from r = 0.13 to r = 0.34, demonstratingsmall-to-moderate effect size estimates. Significance levels from the weighted Stouffer combined tests for beneficial outcomes weresignificant for linkages 3 (multiple disciplines), 6 (symptoms or adverse effects), and 9 (end-of-life care). Weighted effect sizeestimates for beneficial outcomes ranged from r = 0.17 to r = 0.34. Tests for heterogeneity of statistical tests and effect size werenonsignificant in all cases, indicating that the pooled studies provided common estimates of significance and population effect sizes. Sufficient data were not available in the literature to conduct Mantel-Haenszel analyses on these linkages.
Metaanalysis was not performed on linkage 4 (indirect drug delivery systems) for either efficacy or outcomes because literature wasnot conducive to an appropriate assessment. The literature did not consistently report analgesic requirements of the patients studied,which may vary over time as a function of the natural history of the disease. Lack of concurrent analytical control fortime-of-measurement and cohort effects preclude valid comparisons. However, subgroup analyses indicated that mild adverseoutcomes were associated with the use of weak opioids in comparison to NSAID administration. Weighted Stouffer combined testresults were: Zc = 4.69, P < 0.001; the weighted effect size estimate (r = 0.32) indicated a moderate effect size. The odds of adverseeffects (e.g., sedation, nausea, vomiting) were greater for weak opioids versus NSAID groups (odds ratio 1.95, 99% confidence limits1.45-2.46, Z = 3.10, P < 0.001).
Agreement among Task Force members and two methodologists was established by interrater reliability testing. Agreement levelsusing a Kappa statistic for two-rater agreement pairs were as follows: (1) type of study design, k = 0.37-0.67; (2) type of analysis, k =0.47-0.72; (3) evidence linkage assignment, k = 0.47-0.96; and (4) literature inclusion for database, k = 0.35-1.00. Three-raterchance-corrected agreement values were: (1) design, Sav = 0.46, Var (Sav) = 0.008; (2) analysis, Sav = 0.63, Var (Sav) = 0.006; (3)linkage identification, Sav = 0.64, Var (Sav) = 0.005; and (4) literature database inclusion, Sav = 0.53, Var (Sav) = 0.030. These valuesrepresent moderate to high levels of agreement.
The findings of the literature analyses were supplemented by the opinions of Task Force members as well as by surveys of theopinions of a panel of consultants with expertise in cancer pain management (n = 72). The rate of return of the surveys was 81% (n =58 of 72). The percentage of consultants supporting each linkage is reported in supportive of the linkages (i.e., agreed that they provided analgesic benefit, reduced risk of adverse outcomes, improved othercancer-related symptoms, improved quality of life, and were important issues for the guidelines to address).
The feasibility of implementing these guidelines into clinical practice was assessed by an opinion survey of the cancer pain consultantpanel (n = 71). Rate of return of the survey was 65% (n = 46 of 71). The mean number of patients treated annually by the consultantswas reported to be 557.5 (min/max = 10/5,000). Responses for feasibility of implementation of the guidelines were as follows: (1)Ninety-one percent (n = 42 of 46) of these consultants indicated that implementation of the guidelines would not result in the need topurchase new equipment, supplies, or pharmaceuticals. (2) Among the four respondents who stated that purchases would berequired, the median anticipated cost was $25,000 (mean $24,625; range $13,500-35,000).
The consultants were asked to indicate which, if any, of the evidence linkages would change their clinical practices if the guidelineswere instituted. The percent of consultants expecting no change associated with each linkage were as follows: comprehensiveevaluation, 76%; longitudinal monitoring, 78%; multiple disciplines, 89%; administration of systemic opioids, 100%; neuraxial drugdelivery, 87%; neurolytic techniques, 87%; management of symptoms/adverse effects, 89%; psychosocial factors, 89%, use ofparenteral therapy, 94%, end-of-life care, 80%, and pediatric pain management, 83%.
Eighty percent of the respondents indicated that the guidelines would have no effect on the amount of time spent on a typical case. None reported that the guidelines would reduce the amount of time spent per case. For all respondents, the mean increase in theamount of time spent on a typical case was 7.1 min (range 0-120 min). Of the 20% of respondents who reported an anticipatedincrease in time spent on a typical case, the mean was 36.1 min (range 10-120 min).
Readers with special interest in the statistical analyses used in establishing these guidelines can receive further information by writingto the American Society of Anesthesiologists: 520 North Northwest Highway, Park Ridge, Illinois 60068-2573. Appendix 2. Adverse Drug Effects from Opioid Therapies
Tolerance, physical dependence, and addiction are concerns expressed by patients and physicians and must be understood tooptimize therapy.
Tolerance refers to the progressive decline in the potency of an opioid with continued use, such that increasingly greater
doses are needed to achieve the same degree of analgesia. The phenomenon is characteristic of opioids as a class ofanalgesics and is receptor-mediated. Clinical observations confirm that most patients with stable pain do not require doseescalation to maintain relief. Hence, tolerance is seldom the "driving force" for dose escalation. When tolerance to an opioid
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develops, incomplete cross-tolerance to other opioids concomitantly develops. In such cases, another opioid can besubstituted to provide better analgesia.
Physical dependence does not imply addiction. Physical dependence is a physiologic state characterized by withdrawal
(abstinence syndrome) after abrupt discontinuation of an opioid.
Addiction is a psychological and behavioral syndrome characterized by compulsive drug-seeking behavior (among other
behaviors), loss of control over drug use, and continued use despite harm. Addiction implies compulsive behavior andpsychological dependence. This is exceedingly rare among cancer patients who are given opioids. Tolerance (apharmacologic property of a class of drugs) and physical dependence (a physiologic effect characteristic of this class ofdrugs) are conceptually and phenomenologically distinct from addiction.
Constipation is highly prevalent among patients receiving chronic treatment with opioids. All patients with an increased risk fo
constipation should receive prophylactic therapy. Clinical scenarios or syndromes with an increased risk for the developmentof constipation include: (1) cachexia and/or debilitation, (2) poor performance status (especially the bedridden patient), (3)intraabdominal neoplasm, (4) a history of prior abdominal radiation, (5) autonomic neuropathy, (6) poor fluid intake, and (7)the concurrent use of constipating agents. A stool softener (e.g., docusate) often is used in combination with bulk, osmotic, orstimulant cathartics.
Sedation is a common adverse effect associated with the analgesic therapy of cancer pain.
Nausea and vomiting are usually uncommon and transitory in patients undergoing opioid titration. Persistent nausea is rare,
Mental clouding or cognitive impairment can vary from mild mental clouding to frank delirium. Mental clouding may occur
Myoclonus, pruritus, and urinary retention occur infrequently in patients receiving chronic opioid therapy.
Respiratory depression is rare in the cancer patient receiving chronic opioid therapy and occurs in association with obtundation andbradypnea. Respiratory depression can occur with abrupt resolution of pain and inadequate reduction of opioid dosage aftersuccessful neuroablation. If respiratory depression occurs in a patient taking stable opioid doses without abrupt resolution of pain dueto a major therapeutic maneuver, an explanation other than opioid toxicity should be sought (e.g., pulmonary embolism). Reversal ofrespiratory problems with naloxone only signifies that an opioid was contributing to the respiratory problem. Reversal of respiratorydepression with naloxone does not obviate the need to consider other possible etiologies or pursue further evaluation. Template 3. Drug Delivery Systems Method of Access to the "Receptor"*
Indirect (via blood-borne carriage, i.e., systemic analgesia)** Direct***
Via systemic absorption Neuraxial drug delivery Via depot formation Neuroablation Intravenous administration
*Neural tissue. **Indirect (systemic) delivery systems rely on the transport of an analgesic to the receptor site in neural tissue by the blood. Access to the blood may be achieved by systemic absorption, formation of a depot with sustained release, and instillation intothe blood. ***Direct drug delivery systems involve administration of an agent to the neuraxis (i.e., in proximity to the receptor) or in thevicinity of "target" neural tissue. Template 6 Opiod Analgesics Commonly Used to Manage Cancer Pain* Dose Equivalence Generic Name Proprietary Name Comments **,*** (mg) Opiods conventionally used to manage mild to moderate pain
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With the exception ofcodeine, these opioids are
compounded with aspirin oracetaminophen, whichimposes a dosage ceiling. Opioids conventionally used to manage moderate to severe pain
Especially useful for initialdose titration and prn
Often compounded withadjuvants for moderate pain.
Used as a single entity forsevere pain. Sustainedrelease form is available.
stable pain, especially withGI dysfunction
Inexpensive, but long,variable half-life may
complicate titration andpredispose to toxicity
Inexpensive, but long,variable half-life may
complicate titration andpredispose to toxicity
*This list is partial and based on commonly used U.S. formulations. Meperidine and the agonist-antagonist opioids are notincluded in the table. Meperidine may produce seizures because of accumulation of the normeperidine breakdown productduring chronic administration. This is of particular importance in the elderly and in patients with abnormal renal function. Theagonist-antagonist opioids have ceiling and dysphoric effects and may precipitate withdrawal in patients chronically receivingpure agonist opioids. **Dose equivalencies are approximate. ***When converting between drugs or routes of administration, it is recommended to reduce the calculated dose by 25-50% toaccount for incomplete cross-tolerance. (Based on clinical observation, methadone dose should be reduced by 75%.)Appropriate titration of dosage should then be performed as clinically indicated.
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Template 7. Commonly Used Adjuvant Analgesics Class (examples) Usual Indications
Neuropathic pain, particularly lancinating or paroxysmal pain
Tumor invasion of neural tissue, elevated intracranial pressure,
spinal cord compression, additional effects (mood elevation,antiemesis, appetite stimulation)
Occasionally useful for musculoskeletal pain
Decrease sedation due to opioid analgesia
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Table A1. Statistical Summary: Combined Test Results Analgesic efficacy
Linkage 3. Involvement of specialists in multiple disciplines
Linkage 5a. Epidural and subarachnoid drug delivery
Linkage 3. Involvement of specialists from multiple disciplines
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Linkage 6. Management of side effects (primary disease and treatment)
Table A2. Consultant Responses to Evidence Linkages Survey (n = 58) Analgesic Improved Improved Quality Linkages Reduced Risk Important Topic Symptoms (%Supportive) (%Supportive) (%Supportive) (%Supportive) (%Supportive)
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J. Plant Physiol. 159. 567 – 584 (2002) Urban & Fischer Verlaghttp://www.urbanfischer.de/journals/jpp toxicity in higher plants: a critical review Division of Life Sciences, University of Toronto, 1265 Military Trail, Scarborough, Ontario M1C 1A4, CanadaReceived December 14, 2001 · Accepted February 22, 2002 Abstract 4 ) toxicity is an issue of global ecological and economic impo
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