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Breakthrough cancer pain (BTcP) is an episode of severe pain that "breaks through" a period of persistent pain at least partly controlled by a stable opioid regimen. Although mentioned in the literature decades ago, it has been only 25 years since the first effort to define and measure it. Controversy about the definition of BTcP continues despite an international effort to achieve consensus. Nevertheless, common approaches to measurement of BTcP have led to a robust literature, including many surveys that have described prevalence, characteristics, and association with adverse outcomes. Measurement also has been important for clinical trials of new drug formulations specifically designed for BTcP. Several approaches have been reported in the literature, although most of them have never been substantiated with appropriate studies. Administration of an opioid as needed is the most common treatment. Twenty-five years of research has produced a more refined understanding of the safety and efficacy of oral opioids in this context, and provided the clinical trials data necessary to attain regulatory approval of multiple new formulations specifically developed for BTcP. Transmucosal formulations of fentanyl may provide meaningful analgesia within 5 to 15 minutes. Given the difference in cost, transmucosal formulations should be considered in a subset of patients with BTcP, including those with pain that are not adequately controlled with an oral drug and those with distress associated with the rapid pain onset. The long-term use of opioids for BTcP remains to be clarified. Future studies should assess the potential of personalized treatment of BTcP.

During long-term opioid therapy for chronic noncancer pain, monitoring medication adherence of patients with a history of aberrant opioid medication-taking behaviors (AMTB) is an essential practice. There is limited research, however, into the concordance among existing monitoring tools of self-report, physician report, and biofluid screening. This study examined associations among patient and provider assessments of AMTB and urine drug screening using data from a randomized trial of a cognitive-behavioral intervention designed to improve medication adherence and pain-related outcomes among 110 opioid-treated patients with chronic pain who screened positive for AMTB and were enrolled in a pain program. Providers completed the Aberrant Behavior Checklist (ABC) and patients completed the Current Opioid Misuse Measure (COMM) and the Chemical Coping Inventory (CCI). In multivariate analyses, ABC scores were compared with COMM and CCI scores, while controlling for demographics and established risk factors for AMTB, such as pain severity. Based on clinical cutoffs, 84% of patients reported clinically significant levels of AMTB and providers rated 36% of patients at elevated levels. Provider reports of AMTB were not correlated with COMM or CCI scores. However, the ABC ratings of experienced providers (nurse practitioners/attending physicians) were higher than those of less experienced providers (fellows) and were correlated with CCI scores and risk factors for AMTB. Associations between patient- and provider-reported AMTB and urine drug screening results were low and largely nonsignificant. In conclusion, concordance between patient and provider reports of AMTB among patients with chronic pain prescribed opioid medication varied by provider level of training.

The National Breakthrough Pain Study is a large observational study that assessed breakthrough pain (BTP) in a population of commercially insured community-dwelling patients with opioid-treated chronic pain. Eligible patients were identified from an administrative claims database, and consenting patients were asked to complete a structured telephone interview and several validated questionnaires. Questionnaires assessed pain interference with function (Brief Pain Inventory-Short Form), health status (Short Form 12 [SF-12] Health Survey), disability (Sheehan Disability Scale), work performance (World Health Organization Health and Work Performance Questionnaire), and mood (Generalized Anxiety Disorder-7 Screener [GAD-7] and Patient Health Questionnaire-2 [PHQ-2]). Of 2198 patients interviewed, 1278 patients had persistent pain controlled with opioid therapy; 1023 (80%) of these patients reported BTP. Patients had a median of 2.0 episodes of BTP per day (range, 1-50) and a median duration of BTP of 45 minutes (range, 1-720). Compared with patients without BTP, patients with BTP had more pain-related interference in function (Brief Pain Inventory, mean ± SD: 34.2 ± 15.6 vs 25.0 ± 15.7 [P < 0.001]), worse physical health (SF-12 physical component score: 29.9 ± 9.6 vs 35.1 ± 10.4 [P < 0.001]) and mental health (SF-12 mental component score: 47.4 ± 11.3 vs 49.3 ± 10.4 [P < 0.001]), more disability (Sheehan Disability Scale global impairment score: 15.1 ± 9.1 vs 10.6 ± 8.5; World Health Organization Health and Work Performance Questionnaire absolute absenteeism: 12.4 ± 59.9 vs 7.7 ± 44.9 hours [both P < 0.001]), and worse mood (GAD-7 score: 7.4 ± 5.9 vs 5.9 ± 5.4; PHQ-2 anhedonia score: 1.2 ± 1.1 vs 0.9 ± 1.0 [both P < 0.001]). In this population of community-dwelling patients with opioid-treated chronic pain, BTP was highly prevalent and associated with negative outcomes. This burden of illness suggests the need for specific treatment plans.

This randomized, double-blind, crossover study assessed the efficacy and tolerability of a new rapid onset nasal fentanyl formulation (Fentanyl Pectin Nasal Spray; FPNS) for breakthrough cancer pain (BTCP). Eighty-three of 114 patients experiencing one to four BTCP episodes/day while taking ≥60 mg/day of oral morphine or equivalent successfully identified an effective dose of FPNS during a titration phase and entered a double-blind phase in which 10 BTCP episodes were treated with this effective dose (7) or placebo (3). Compared with placebo, FPNS significantly improved mean summed pain intensity difference (SPID) from 10 min (P<0.05) until 60 min (P<0.0001), including the primary endpoint at 30 min (P<0.0001). FPNS significantly improved pain intensity (PI) scores as early as 5 min (P<0.05); pain intensity difference (PID) from 10 min (P<0.01); and pain relief (PR) scores from 10 min (P<0.001). More patients showed a clinically meaningful (≥ 2-point reduction in PI) pain reduction from 10 min onward (P ≤ 0.01) and 90.6% of the FPNS-treated versus 80.0% of placebo-treated BTCP episodes did not require rescue medication (P<0.001). Approximately 70% of patients were satisfied or very satisfied with the convenience and ease of use of FPNS. Only 5.3% of patients withdrew from treatment due to adverse events, no significant nasal effects were reported, and 87% of patients elected to continue open-label treatment post-study. In this short-term study, FPNS was safe, well tolerated, and rapidly efficacious for BTCP., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

Oral transmucosal fentanyl citrate (OTFC); Actiq) is a drug delivery formulation used for management of breakthrough cancer pain. Previous studies with open-label comparisons indicated OTFC was more effective than patients' usual opioid for breakthrough pain. The objective of this study was to compare OTFC and morphine sulfate immediate release (MSIR) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen. This double-blind, double-dummy, randomized, multiple crossover study was conducted at 19 US university- and community-based hospitals and clinics and comprised 134 adult ambulatory cancer patients. Patients were receiving a fixed scheduled opioid regimen equivalent to 60-1000 mg/day oral morphine or 50-300 microg/h transdermal fentanyl, were using a 'successful' MSIR dose (15-60 mg) as defined by entry criteria, and were experiencing 1-4 episodes of breakthrough pain per day. In open-label fashion, OTFC was titrated such that a single unit (200-1600 microg) provided adequate pain relief with acceptable side effects. Successfully titrated patients entered the double-blind phase of the study and received ten prenumbered sets of randomized capsules and oral transmucosal units. Five sets were the successful OTFC dose paired with placebo capsules, and five sets were placebo OTFC paired with capsules containing the successful MSIR dose. Patients took one set of study medication for each episode of target breakthrough pain. Pain intensity (PI), pain relief (PR) and global performance of medication (GP) scores were recorded. Pain intensity differences (PID) were calculated and 15-min PID was the primary efficacy variable. Adverse events were recorded. Sixty-nine percent of patients (93/134) found a successful dose of OTFC. OTFC yielded outcomes (PI, PID, and PR) at all time points that were significantly better than MSIR. GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study. Somnolence, nausea, constipation, and dizziness were the most common drug-associated side effects. In conclusion, OTFC was more effective than MSIR in treating breakthrough cancer pain.

The purpose of this study was to determine the levels of change on standard pain scales that represent clinically important differences to patients. Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious. Differences between groups, as summarized by a change in mean values over time, can be difficult to apply to clinical care. Baseline scores vary widely and group mean differences could reflect large changes in a few patients, small changes in many patients, or any combination of these outcomes. Determination of the proportion of patients who have a clinically important improvement in their pain would provide a more interpretable result with direct clinical implications. However, determining a clinically important outcome requires information about the degree of change over time that is clinically important. Data from the titration phase of a multiple cross-over randomized clinical trial of oral transmucosal fentanyl citrate (OTFC) for the treatment of cancer-related breakthrough pain were re-analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief. The scales evaluated were absolute pain intensity difference (PID, 0-10 scale), percentage pain intensity difference (PID%, 0-100% scale), pain relief (PR, 0 (none), 1 (slight), 2 (moderate), 3 (lots), 4 (complete)), sum of the pain intensity difference (SPID over 60 min), percentage of maximum total pain relief (% Max TOTPAR over 60 min), and global medication performance (0 (poor), 1 (fair), 2 (good), 3 (very good), 4 (excellent)). Adequate relief was defined by the patient's decision not to use another dose of opioid medication as a rescue, in addition to the study medication, to treat each painful episode. One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain. The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief, with balanced sensitivity and specificity. The best cut-off point for both the % Max TOTPAR and the PID% was 33%. The best cut-off points for the absolute scales were absolute pain intensity difference of 2, pain relief of 2 (moderate), and SPID of 2. The global medication performance of 2 (good) had excellent values as well. This study presents data-derived cut-off points for the changes in several pain scales, each reflecting the clinically important improvement for patients treating breakthrough cancer pain episodes with OTFC. Confirmation in other patient populations and different pain syndromes will be needed. The use of consistent clinically important cut-off points as the primary outcome in future pain therapy clinical trials will enhance their validity, comparability, and clinical applicability.

The optimal assessment of cancer pain includes a detailed description of pain characteristics and classification by both syndrome and likely mechanisms. In the clinical setting, the interpretation of this information is aided by knowledge of the available clinical experiences on these aspects of the pain. Unfortunately, existing data are limited. There have been few large surveys of cancer pain characteristics and syndromes, and comparative data from patients in different parts of the world are entirely lacking. To better define the characteristics of cancer pain syndromes the Task Force on Cancer Pain of the International Association for the Study of Pain (IASP) conducted a prospective, cross-sectional, international, multicenter survey of pain specialists and their patients. From a total of 100 clinicians who described themselves as cancer pain practitioners in the IASP membership directory, 51 agreed to participate in the survey and a total of 58 provided data. These clinicians resided in 24 countries and evaluated a total of 1095 patients with severe cancer pain mostly requiring opioid medication, using a combination of patient-rated and observer-rated measures. The patient-rated scales comprised a pain intensity measure chosen from the brief pain inventory. The observer-rated information included demographic and tumor-related data, and responses on checklists of pain syndromes and pathophysiologies. Patients were heterogeneous in terms of demographics and tumor-related information. More than 76% had a Kamofsky performance status score < or = 70. Almost one-quarter of the patients experienced two or more pains. A large majority of the patients (92.5%) had one or more pains caused directly by the cancer; 20.8% of patients had one or more pains caused by cancer therapies. The average (SD) duration of pain was 5.9 (10.5) months. Approximately two-thirds of patients (66.7%) reported that the worst pain intensity during the day prior to the survey was > or = 7 on a 10-point numeric scale. The factors that were univariately associated with higher pain intensity included the presence of breakthrough pain, somatic pain or neuropathic pain, age younger than 60 years, and lower performance status score. A multivariate model suggested that the presence of breakthrough pain, somatic pain, and lower performance status were the most important predictors of intense pain. Pains that were inferred by the treating clinician to be nociceptive and due to somatic injury occurred in 71.6% of the patients. Pains labeled nociceptive visceral were noted in 34.7% and pains inferred to have neuropathic mechanisms occurred in 39.7%. In a broad classification, the major pain syndromes comprised bone or joint lesions (41.7% of patients), visceral lesions (28.1%), soft tissue infiltration (28.3%), and peripheral nerve injuries (27.8%). Twenty-two types of pain syndromes were most prevalent. Large differences in the diagnosis of breakthrough pain by clinicians of different countries suggest that this phenomenon is either defined or recognized differently across countries. These data confirm, in segment of the cancer population experiencing severe pain, in different parts of the world, that cancer pain characteristics, syndromes and pathophysiologies are very heterogeneous. Predictors of worsening pain can be identified. The data provide a useful context for the interpretation of pain-related information acquired in both clinical and research settings. They suggest the need for future studies and the potential usefulness of a written checklist for cancer pain syndromes and pathophysiologies.

Few surveys have been performed to define the characteristics and impact of breakthrough pain in the cancer population. In this cross-sectional survey of inpatients with cancer, patients responded to a structured interview (the Breakthrough Pain Questionnaire) designed to characterize breakthrough pain, and also completed measures of pain and mood (Memorial Pain Assessment Card (MPAC)), pain-related interference in function (Brief Pain Inventory (BPI)), depressed mood (Beck Depression Inventory (BDI)), and anxiety (Beck Anxiety Inventory (BAI)). Of 178 eligible patients, 164 (92.2%) met the criteria for controlled background pain. The median age was 50.6 years (range 26 to 77 years), 52% were men, and 80.6% were Caucasian. Tumor diagnoses were mixed, 75% had metastatic disease, 65% had pain caused directly by the neoplasm, and a majority had mixed nociceptive-neuropathic pain. The median Karnofsky Performance Status score was 60 (range 40 to 90). Eighty-four (51.2%) patients had experienced breakthrough pain during the previous day. The median number of episodes was six (range 1 to 60) and the median interval from onset to peak was 3 min (range 1 s to 30 min). Although almost two-thirds (61.7%) could identify precipitants (movement 20.4%; end-of-dose failure 13.2%), pain was unpredictable in a large majority (78.2%). Patients with breakthrough pain had more intense (P < 0.001) and more frequent (P < 0.01) background pain than patients without breakthrough pain. Breakthrough pain was also associated with greater pain-related functional impairment (difference in mean BPI. P < 0.001), worse mood (mood VAS, P < 0.05; BDI, P < 0.001), and more anxiety (BAI, P < 0.001). Multivariate analysis confirmed that breakthrough pain independently contributed to impaired functioning and psychological distress. These data confirm that cancer-related breakthrough pain is a prevalent and heterogeneous phenomenon. The presence of breakthrough pain is a marker of a generally more severe pain syndrome, and is associated with both pain-related functional impairment and psychological distress. The findings suggest the need for further studies of breakthrough pain and more effective therapeutic strategies.

Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There have been no controlled trials of other treatments for this condition. To evaluate the safety and efficacy of ascending doses of OTFC, a novel controlled dose titration methodology was developed that applied blinding and randomization procedures to the evaluation of recurrent pains in the home environment. The study was a multicenter, randomized, double-blind dose titration study in ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least one episode per day of breakthrough pain and had achieved at least partial relief of this pain by use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 microg OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 800, 1200 or 1600 microg of fentanyl citrate were available for the study. The unit dose was titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain could be treated with the single unit dose, titration was ineffective at a 1600 microg unit dose, or 20 days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the time according to a pre-defined randomization schedule accessible only to an unblinded study pharmacist. Main outcome measures included, numeric or categorical measures of pain intensity, pain relief, and global assessment of drug performance. Dose response relationships were found suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients were successfully titrated. There was no relationship between the total daily dose of the fixed schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. Although the study was not designed to provide a definitive comparison between OTFC and the usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse effects of the OTFC were typically opioid-related, specifically somnolence, nausea and dizziness. Very few adverse events were severe or serious. This study demonstrated the feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit dose capable of providing adequate analgesia. If the lack of a relationship between the effective OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the clinical use of this formulation. Further investigation of OTFC as a specific treatment for breakthrough pain is warranted.

Ambulatory AIDS patients participating in a quality of life study were recruited for an assessment of pain syndromes. Of 274 patients with pain, 151 (55%) consented to the assessment which included a clinical interview, neurologic examination, and review of medical records. The number, type, and etiology of pains were evaluated in terms of risk factors, age, sex, CD4+ lymphocyte count, and performance status. The average number of pains per patient was 2.7 (range, 1-7), yielding a total of 405 pains. The most common pain diagnoses were headache (46% of patients; 17% of all pains), joint pain (31% of patients; 12% of pains), pain due to polyneuropathy (28% of patients; 10% of pains), and muscle pain (27% of patients; 12% of pains). Pathophysiology was inferred for all pain syndromes (except for headache), 45% of pain syndromes were somatic in nature, 15% were visceral, 19% were neuropathic, and 4% were unknown, psychogenic, or idiopathic; 17% of pains were classified as headache, hence pathophysiology could not be determined. Pain resulted from diverse etiologies, including the direct effects of HIV/AIDS-related conditions (30%) pre-existing unrelated conditions (24%), and therapies for HIV/AIDS and related conditions (4%). The latter category, pain related to HIV therapies, occurred in 11% of patients. In 37% of the pains, the etiology could not be determined from the information available. In univariate analyses, lower CD4+ cell counts were significantly associated with polyneuropathy (P < 0.05) and headache (P < 0.05), and female gender was significantly associated with the presence of headache (P < 0.05) and radiculopathy (P < 0.001). These data confirm the diversity of pain syndromes in AIDS patients, clarify the prevalence of common pain types, and suggest associations between specific patient characteristics and pain syndromes. The large proportion of patients who could not be given a diagnosis underscores the need for a careful diagnostic evaluation of pain in this population.

The characteristics and impact of pain were evaluated in a prospective cross-sectional survey of 438 ambulatory AIDS patients recruited from health care facilities in New York City. More than 60% of the patients reported 'frequent or persistent pain' during the 2 wks preceding the study. Patients with pain reported an average of 2.5 different pains. On the 0-10 numerical scale of the Brief Pain Inventory (BPI), mean pain intensity 'on average' was 5.4 (SD = 2.2; range = 0-10), and mean pain 'at its worst' was 7.4 (SD = 2.0; range = 1-10). The pain-related functional interference index (sum of the seven item BPI subscale) was 42.6 (SD = 17.2; range = 0.70). Demographic variables were not associated with the presence of pain, but the number of current HIV-related symptoms, treatment for HIV-related infections, and the absence of antiretroviral medications were significantly associated with the presence of pain. Female gender, non-Caucasian race, and number of HIV-related physical symptoms were significantly associated with pain intensity. Presence of pain and increasing pain intensity were significantly associated with greater impairment in functional ability (Karnofsky Performance Status, BPI functional interference index) and physical symptom distress (Memorial Symptom Assessment Scale). Results demonstrate high levels of pain and pain-related functional impairment among patients with AIDS. The presence and intensity of pain are associated with more advanced HIV disease and pain intensity is also associated with demographic factors (gender, race).

The relationships among pain, psychological distress and other quality of life concerns were examined through a prospective cross-sectional survey of 438 ambulatory AIDS patients recruited from health care facilities in New York City. In this sample, 274 (62.6%) patients reported frequent or persistent pain during the prior 2 wks. Patients with and without pain completed a questionnaire packet that included measures of psychological symptom distress (Brief Symptom Inventory and the Psychological Distress Subscale of the Memorial Symptom Assessment Scale), depression (Beck Depression Inventory and Beck Hopelessness Scale), social support (Social Support Questionnaire), and overall quality of life (Functional Living Index-Cancer, modified for AIDS). Multivariate analyses (MANOVA, multiple regression) revealed significant associations between the presence and intensity of pain and scores on the measures of psychological distress, depression, hopelessness, and quality of life (P < 0.0001 for most analyses). Perceived adequacy of social support was also significantly associated with lower levels of psychological distress and depression, and better quality of life. These results demonstrate the significant relationships between pain, psychological well-being, and quality of life, and affirm the need to provide adequate treatment of pain in patients with AIDS.

The nature and duration of pain associated with herpes zoster is highly variable. This review of research on pain in acute herpes zoster and postherpetic neuralgia (PHN) explores those observations relevant to the definition and pathogenesis of PHN and the design of treatment trials. A model for the pathogenesis of PHN is presented, which gains support from studies of risk factors. Several directions for future research are identified.

Pain is highly prevalent in individuals with HIV disease, yet is often overlooked as a symptom requiring clinical intervention. We evaluated the adequacy of analgesic management for pain and identified predictors of pain undertreatment in a sample of 366 ambulatory AIDS patients using a prospective cross-sectional survey design. Two hundred and twenty-six of the 366 ambulatory AIDS patients surveyed reported "persistent or frequent" pain over the 2 week period prior to the survey. Adequacy of analgesic therapy was assessed using the Pain Management Index (PMI - a measure derived from the Brief Pain Inventory) and the type and frequency of analgesic medications prescribed for pain. Results indicated that nearly 85% of patients were classified as receiving inadequate analgesic therapy based on the PMI. Less that 8% of the 110 patients who reported "severe" pain were prescribed a "strong" opioid (e.g., morphine), as suggested by published guidelines. Adjuvant analgesic drugs (e.g., antidepressant medications) were prescribed in only 10% of the patients. Women, less educated patients, and patients who reported injection drug use as their HIV transmission risk factor were most likely to have received inadequate analgesic therapy. These results demonstrate the alarming degree of undertreatment of pain in ambulatory patients with AIDS, and indicates the need to improve the management of AIDS-related pain in this underserved population. Future research should elucidate the factors that impede adequate pain management in order to overcome obstacles to adequate treatment.

The active morphine metabolite, morphine-6-glucuronide (M-6-G), may contribute to both the analgesia and the adverse effects observed during morphine (MOR) therapy. To evaluate the relationship between M-6-G and adverse effects, we measured steady-state plasma concentrations of MOR and M-6-G and concurrently noted the presence or absence of moderate to severe cognitive impairment or myoclonus in 109 cancer patients who were receiving either oral (n = 71) or parenteral (n = 38) morphine. MOR and M-6-G plasma concentrations were determined by HPLC with electrochemical detection. The presence of cognitive impairment or myoclonus was analyzed in relation to molar M-6-G/MOR ratio, age, morphine dose, the use of other centrally acting drugs, renal function (blood urea nitrogen (BUN) and serum creatinine), hepatic function (serum bilirubin, serum glutamic oxalacetic transaminase (SGOT), and alkaline phosphotase) and serum lactate dehydrogenase (LDH). The patient population consisted of 60 women and 49 men. The mean age was 51.5 years (range: 10-85 years). The mean morphine dose (total dose-prior 48 h) was 486 mg (range: 40-4800 mg) for the oral group and 931 mg (range: (10-9062 mg) for the parenteral group. The mean molar M-6-G/MOR ratios were 6.1 (SD: 18.2; range: 0.01-153.3) for the oral treatment group and 2.7 (SD: 4.16; range: 0.05-23.8) for the parenteral treatment group. Overall, the M-6-G/MOR ratio demonstrated a moderate but significant correlation with BUN (r = 0.4; P < 0.001) and creatinine (r = 0.45; P < 0.001) levels, but not with the other clinical variables examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Although it is widely appreciated that patients can demonstrate highly variable responses to different opioid drugs, there have been few detailed descriptions of this phenomenon. To illustrate this variability, we present 5 patients, 4 with cancer pain and 1 with non-malignant pain, who underwent dose titration with more than 1 opioid and developed markedly different responses to each. In every case, dose escalation led to successful treatment with 1 opioid and to intolerable side effects without adequate relief with others. The existence of this individual variability in the response to different opioids has important implications for both clinical practice and current understanding of opioid pharmacology in man. It contradicts the view that any opioid is inherently more efficacious than any other, suggests that patients who fail to obtain adequate pain relief at maximally tolerated doses of 1 opioid may benefit from an alternative drug, and underscores the potential importance of genetic factors as a determinant of opioid response.

To evaluate the importance of a comprehensive evaluation in the management of patients with cancer pain, we surveyed 276 consecutive consultations (226 retrospectively and 50 prospectively) performed by the pain consultant at Memorial Sloan-Kettering Cancer Center. For all consultations, the pain diagnosis, other medical and neurologic diagnoses, investigations and suggested therapeutic interventions were recorded. The pain consultation identified a previously undiagnosed etiology for the pain in 64% of patients in both surveys. Metastatic neoplasm was the most common lesion discovered. In addition, the prospective survey yielded new neurologic diagnoses in 36% of patients and an unsuspected infection in 4%. Eighteen percent of prospectively surveyed patients received radiotherapy, surgery or chemotherapy based on the findings of the pain consultant. These data confirm the importance of a comprehensive neuro-oncologic evaluation in the management of cancer pain. An understanding of oncology, neurology and medicine is critical to assess and treat these patients.

Morphine-6-glucuronide (M-6-G) is an active metabolite of morphine that may contribute to drug effects. To understand better the relationship between morphine and M-6-G in cancer patients receiving chronic therapy, we employed high performance liquid chromatography with electrochemical detection to measure: (1) morphine and M-6-G plasma concentrations following discontinuation of dosing in 2 patients, one receiving oral therapy and the other an intravenous infusion; (2) morphine and M-6-G concentrations in random blood samples taken at apparent steady state from 8 patients, 7 with normal renal function and 1 with mild renal insufficiency, who were receiving continuous morphine infusions; and (3) morphine and M-6-G concentrations in random blood samples taken over a period of weeks from 4 patients, 2 with stable and 2 with declining renal function. Results demonstrated a slightly slower decline in plasma M-6-G than morphine concentrations following drug discontinuation, as would be expected for metabolite and parent relationship; roughly similar M-6-G: morphine ratios (mean molar ratio = 1.22) across a broad range of morphine doses in patients with normal renal function; and an increase in this ratio over time in patients with progressive renal dysfunction. These data illustrate the kinetics of M-6-G in cancer patients receiving chronic morphine therapy and confirm the importance of renal function in determining the concentration of the metabolite.

In recent years, the observation that the response of patients to opioid drugs may be influenced by properties inherent in the pain or pain syndrome, such as its pathophysiology, has evolved into the belief that certain types of pain, e.g., neuropathic pains, may be unresponsive to these drugs. This concept has important implications for both clinical practice and basic understanding of opioid mechanisms. We critically evaluate opioid responsiveness, particularly as it relates to neuropathic pain, and propose a clinically relevant definition and a paradigm for its investigation. The paradigm is illustrated by analgesic responses to opioid infusion in 28 patients with neuropathic pains and by a detailed presentation of the pharmacokinetic and pharmacodynamic relationships in one of these patients, whose central pain responded promptly to an infusion of hydromorphone. From this analysis, we hypothesize that (1) opioid responsiveness in man can be defined by the degree of analgesia achieved during dose escalation to either intolerable side effects or the occurrence of 'complete' or 'adequate' analgesia; (2) opioid responsiveness is a continuum, rather than a quantal phenomenon; (3) opioid responsiveness is determined by a diverse group of patient characteristics and pain-related factors, as well as drug-selective effects; and (4) a neuropathic mechanism may reduce opioid responsiveness, but does not result in an inherent resistance to these drugs. Given the complexity of factors contributing to opioid responsiveness and the observation that outcome cannot be reliably predicted, opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. Both the clinical use of opioids and paradigms to investigate opioid responsiveness should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects.

In the cancer population, the term breakthrough pain typically refers to a transitory flare of pain in the setting of chronic pain managed with opioid drugs. The prevalence and characteristics of this phenomenon have not been defined, and its impact on patient care is unknown. We developed operational definitions for breakthrough pain and its major characteristics, and applied these in a prospective survey of patients with cancer pain. Data were collected during a 3 month period from consecutive patients who reported moderate pain or less for more than 12 h daily and stable opioid dosing for a minimum of 2 consecutive days. Of 63 patients surveyed, 41 (64%) reported breakthrough pain, transient flares of severe or excruciating pain. Fifty-one different pains were described (median 4 pains/day; range 1-3600). Pain characteristics were extremely varied. Twenty-two (43%) pains were paroxysmal in onset; the remainder were more gradual. The duration varied from seconds to hours (median/range: 30 min/1-240 min), and 21 (41%) were both paroxysmal and brief (lancinating pain). Fifteen (29%) of the pains were related to the fixed opioid dose, occurring solely at the end of the dosing interval. Twenty-eight (55%) of the pains were precipitated; of these, 22 were caused by an action of the patient (incident pain), and 6 were associated with a non-volitional precipitant, such as flatulence. The pathophysiology of the pain was believed to be somatic in 17 (33%), visceral in 10 (20%), neuropathic in 14 (27%), and mixed in 10 (20%). Pain was related to the tumor in 42 (82%), the effects of therapy in 7 (14%), and neither in 2 (4%). Diverse interventions were employed to manage these pains, with variable efficacy. These data clarify the spectrum of breakthrough pains and indicate their importance in cancer pain management.

Thirty-eight patients maintained on opioid analgesics for non-malignant pain were retrospectively evaluated to determine the indications, course, safety and efficacy of this therapy. Oxycodone was used by 12 patients, methadone by 7, and levorphanol by 5; others were treated with propoxyphene, meperidine, codeine, pentazocine, or some combination of these drugs. Nineteen patients were treated for four or more years at the time of evaluation, while 6 were maintained for more than 7 years. Two-thirds required less than 20 morphine equivalent mg/day and only 4 took more than 40 mg/day. Patients occasionally required escalation of dose and/or hospitalization for exacerbation of pain; doses usually returned to a stable baseline afterward. Twenty-four patients described partial but acceptable or fully adequate relief of pain, while 14 reported inadequate relief. No patient underwent a surgical procedure for pain management while receiving therapy. Few substantial gains in employment or social function could be attributed to the institution of opioid therapy. No toxicity was reported and management became a problem in only 2 patients, both with a history of prior drug abuse. A critical review of patient characteristics, including data from the 16 Personality Factor Questionnaire in 24 patients, the Minnesota Multiphasic Personality Inventory in 23, and detailed psychiatric evaluation in 6, failed to disclose psychological or social variables capable of explaining the success of long-term management. We conclude that opioid maintenance therapy can be a safe, salutary and more humane alternative to the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.

A 48-year-old woman with a stimulating electrode implanted in the right thalamic nucleus ventralis posterolateralis developed compulsive self-stimulation associated with erotic sensations and changes in autonomic and neurologic function. Stimulation effects were evaluated by neuropsychologic testing, endocrine studies, positron emission tomographic measurements of regional cerebral metabolic rate for glucose, EEG and evoked potentials. During stimulation, vital signs and pupillary diameter increased and a left hemiparesis and left hemisensory loss developed. Verbal functions deteriorated and visuospatial processing improved. Plasma growth hormone concentrations decreased, and adrenocorticotrophic hormone and cortisol levels rose. With stimulation, glucose metabolism increased in both thalami and both hemispheres, reversing baseline right-sided hypometabolism and right-left asymmetries. EEG and both somatosensory and brain-stem auditory evoked potentials remained unchanged during stimulation, while visual evoked potentials revealed evidence of anterior visual pathway dysfunction in the left eye. This case establishes the potential for addiction to deep brain stimulation and demonstrates that widespread behavioral and physiological changes, with concomitant alteration in the regional cerebral metabolic rate for glucose, may accompany unilateral thalamic stimulation.