Norbert Griessinger

Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial

BACKGROUND Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed. OBJECTIVE The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 microg/h) with placebo. METHODS This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 microg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain. RESULTS A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-microg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 microg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid. CONCLUSIONS Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics.

Transdermal buprenorphine in clinical practice--a post-marketing surveillance study in 13,179 patients.

ABSTRACT Objective: The objective of this post-marketing surveillance study was to collect effectiveness and safety data on the labelled use of buprenorphine transdermal patches (Transtec*) under routine clinical conditions. * Transtec is a registered trademark of Grünenthal GmbH, Aachen, Germany Research design and methods: For this open, observational study, patients with moderate to severe cancer or non-cancer pain requiring treatment with an opioid analgesic were recruited at hospitals, outpatient clinics and general practitioners’ practices in Germany. Buprenorphine transdermal patches (35 µg/h, 52.5 µg/h or 70 µg/h) were prescribed at physicians’ discretion in accordance with the products Summary of Product Characteristics (SmPC). Patients assessed their pain relief as ‘very good’, ‘good’, ‘satisfactory’, ‘poor’ or ‘no effect’. Investigators were instructed to report all adverse events throughout the observation period. On completion, effectiveness and tolerability were evaluated for the overall study population, cancer and non-cancer patients, and patients < 70 years and ≥ 70 years. Other analyses assessed pain relief with respect to previous opioid treatment and increased patch strength, and in patients who remained on their original dose. The total observation time was 9 months, and the average individual documented treatment time was 60.8 days. Results: A total of 13 179 patients were evaluated; 3690 (28%) with cancer pain and 9489 (72%) with non‐cancer pain. The most frequent diagnoses in non‐cancer patients were musculoskeletal disorders (77%) and neuropathy (23%). In the great majority of cases (78%), treatment was started with the 35 µg/h patch. The initial dose needed to be increased subsequently only in about 18% of subjects. Buprenorphine transdermal patches provided effective, sustained and dose-dependent analgesia in patients with cancer and non‐cancer pain, irrespective of the patients’ age or pain syndromes. Whereas good or very good pain relief was documented only for 6% of the patients with the initial assessment, this percentage increased to 71% at the first follow‐up and 80% at the final assessment. Fewer than 5% of subjects discontinued treatment owing to unsatisfactory pain relief. Altogether, adverse events were documented for 2874 patients (22%), whereas a relationship with transdermal buprenorphine (adverse drug reactions) was assumed for only 10% (2220 adverse drug reactions in 1330 patients). The tolerability profile was as expected for an opioid and did not vary to a relevant extent with either the patients age or the cause of pain (cancer or non‐cancer). No evidence emerged of any previously unknown side effects. Conclusions: Buprenorphine transdermal patches are well tolerated and effective in the treatment of chronic cancer and non‐cancer pain, irrespective of the patients’ age. There was no clinically relevant development of tolerance.

Attentional and emotional mechanisms related to pain as predictors of chronic postoperative pain: a comparison with other psychological and physiological predictors.

&NA; The present prospective longitudinal study on chronic postoperative pain was conducted to assess the predictive power of attentional and emotional variables specifically assumed to augment pain, such as pain hypervigilance, pain‐related anxiety, pain catastrophizing and attentional biases to pain. Their relevance was determined in comparison with other psychological and physiological predictors (depression, anxiety, somatization, cortisol reactivity, pain sensitivity). In 84 young male patients the predictor variables were assessed one day before surgery (correction of chest malformation). Postoperative outcome (subjective pain intensity and pain‐related disability) was assessed three (N = 84) and six months (N = 78) after surgery. Patients were classified into good and poor outcome groups. Patients with high pain intensity three (25%) or six months (14%) after surgery, differed significantly from those low in pain with regard to their preoperative performance in the dot‐probe task (high attentional bias towards positive words). A sizeable portion (54%) of patients still felt disabled due to pain after three months and a few patients after six months (13%). These patients were those with high preoperative ratings in the Pain Vigilance and Awareness Questionnaire. The few subjectively disabled patients after six months could be identified in addition by low pressure pain and high cold pain thresholds before surgery. An attentional bias towards positive stimuli prior to surgery may indicate a maladaptive coping style, which avoids necessary confrontation with pain and predisposes patients to chronic postoperative pain. Lasting subjectively felt pain‐related disability occurs predominantly in patients with high levels of pain hypervigilance before surgery.

Ein strukturiertes Schmerzinterview für geriatrische Patienten

ZusammenfassungProblemstellung. Die Diagnostik des Schmerzes im Alter wird häufig durch sensorische und kognitive Beeinträchtigungen erschwert, die es den Betroffenen unmöglich machen, standardisierte Fragebögen ohne fremde Hilfe auszufüllen. Es wurde ein strukturiertes Schmerzinterview entwickelt und anhand einer Stichprobe geriatrischer Schmerzpatienten mit und ohne kognitive Beeinträchtigung hinsichtlich Güte und Akzeptanz überprüft. Methode. Das Interview besteht aus 14 Fragen zur Schmerzlokalisation, Schmerzintensität, Schmerzdauer und -persistenz und Beeinträchtigung sowie zu emotionalen und kognitiven Variablen. Ergänzend wird eine Fremdanamnese zu Medikation, vorherigen Behandlungen und Wohnsituation vorgegeben und die Mini-Mental-State-Examination (MMSE) durchgeführt. Daten liegen von 128 Patienten im Alter von 75 Jahren und älter vor, die eine Schmerzeinrichtung aufsuchten. Von ihnen sind 80% Frauen. Ergebnis. Im MMSE liegen 40% der Stichprobe unter dem kritischen Wert ≤23 und müssen somit als deutlich kognitiv beeinträchtigt bezeichnet werden. Diese Patienten vereinen auf sich 36 der 39 fehlenden Angaben, wobei die fehlenden Angaben unter einem MMSE-Wert <10 deutlich zunehmen. Kognitiv Beeinträchtigte geben eine größere funktionale und soziale Einschränkung an als kognitiv Unbeeinträchtigte. Hinsichtlich der Angaben zur Schmerzlokalisation, Schmerzintensität und Schmerzdauer finden sich allerdings keine Unterschiede zwischen beiden Gruppen. Die Merkaufgabe innerhalb der MMSE kann als Screening für kognitive Beeinträchtigung verwendet werden. Patienten, die keinen der 3 einzuprägenden Begriffe erinnern können, vereinen 80% der fehlenden Angaben auf sich und haben einen niedrigen MMSE-Gesamtwert. Schlussfolgerung. Das strukturierte Schmerzinterview kann auch bei kognitiver Beeinträchtigung durchgeführt werden, solange die Patienten verbal kommunizieren können. Erst bei einem MMSE-Wert <10 erweist sich die Interpretation der erhaltenen Daten wegen einer großen Häufigkeit fehlender Angaben nicht mehr als sinnvoll.AbstractBackground. In old age, assessment of pain often is hampered by sensory and cognitive deficits that do not allow the patients to fill in standardized questionnaires without help from significant others. Therefore, as an alternative, we developed a structured pain interview, and examined its properties and acceptance in a sample of geriatric patients with pain. Methods. The interview covers site of pain, intensity of pain, its duration and persistency, pain related disability and, finally, emotional and cognitive variables. In addition, the interviewer addresses significant others to get information about medication, previous treatment, and residence, and administers the Mini-Mental-State-Examination (MMSE). The analysis includes 128 patients of pain centers older than 74 years, of whom 80% are female. Results. Forty percent of the subjects score below the critical MMSE value ≤23 indicative of cognitive impairment. These patients are responsible for 36 out of a total of 39 missing values. A significant increase of missing values is observed in patients with a MMSE score below 10. Cognitive impairment goes along with greater functional and social disability. On the other hand, cognitive impairment is unrelated to localization, intensity, and duration of pain. The memory item of the MMSE can be used as a screening tool for cognitive impairment. Patients, who are unable to recall any of the three objects, comprise 80% of the total of missing values and demonstrate a low MMSE score. Conclusion. As long as geriatric patients are able to communicate verbally, they are most likely to profit from the structured pain interview in spite of existing cognitive impairment. A MMSE score <10 indicates that the interpretation of the data obtained may be difficult, especially due to a high frequency of missing values.

Hypervigilance as Predictor of Postoperative Acute Pain: Its Predictive Potency Compared With Experimental Pain Sensitivity, Cortisol Reactivity, and Affective State

ObjectivesPain hypervigilance—a strong attentional bias toward pain—is thought to accompany chronic pain and modulate pain management. Its usefulness as predisposing factor for the development and maintenance of pain has been discussed. The aim of our study was to demonstrate the predictive power of hypervigilance for the development of acute postoperative pain. MethodsFifty-four young male patients were assessed 1 day before surgery (correction of chest malformation) on a range of psychologic predictors. These predictors included the assessment of hypervigilance (questionnaires as the Pain Catastrophizing Scale, Pain Anxiety Symptom Scale, the Pain Vigilance and Awareness Questionnaire, and the dot-probe task) and affective state, experimental pain sensitivity, and cortisol reactivity. Acute postoperative pain was assessed by ratings of pain intensity 1 week postsurgery and through the amount of analgesics [patient-controlled epidural analgesia (PCEA)] requested during the first days after surgery. ResultsPain intensity was significantly explained (17% explained variance) by hypervigilance, whereas PCEA performance was not (10%). Adding all other predictors led to a significant increase of explained variance (35%) for pain ratings and a nonsignificant increase (19%) for PCEA. A more parsimonious solution with only heat pain threshold added led to a significant increase in explained variance (30%) for pain intensity. Hypervigilance was only moderately correlated with the other predictors. DiscussionHypervigilance proved to be a powerful predictor of subjective acute postoperative pain, but was less useful with regard to the amount of requested analgesics. The overlap with other psychologic predictors (affective state, experimental pain sensitivity, and cortisol reactivity) is sufficiently small to consider hypervigilance a promising supplement in psychologic predictor research.

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end‐stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R = 0.74; P < 0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 μg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

The effects of paracetamol and parecoxib on kidney function in elderly patients undergoing orthopedic surgery.

The common adverse effects of traditional nonsteroidal antiinflammatory drugs on renal function include reductions in renal blood flow, glomerular filtration rate, and sodium and potassium excretion, mainly via inhibition of renal cyclooxygenase. We designed the present study to determine the effects of IV paracetamol or parecoxib on renal function in elderly patients undergoing orthopedic surgery. Seventy-five patients (76 ± 8 yr, mean ± sd) undergoing hip replacement or surgery of the femoral shaft completed this randomized and placebo-controlled study. After their arrival in the postanesthesia care unit, patients received an initial dose of the study medication, paracetamol 1000 mg IV (n = 25), parecoxib 40 mg IV (n = 25), or saline IV (n = 25); subsequent doses were administered for the next 3 days. Opioids were provided as rescue medication. Blood and urine samples were collected before and after surgery, and markers of renal function were determined. During the first 2 h after the initial dose of parecoxib, creatinine clearance was slightly diminished (125 ± 83 to 86 ± 45 mL/min, P < 0.05), whereas no significant decrease of creatinine clearance was observed in the placebo and paracetamol groups. After all treatments, sodium and potassium excretion as well as urine albumin and &agr;-1-microglobulin were transiently increased (group differences: not signicifant). In conclusion, glomerular and tubular functions were transiently affected in all patients after orthopedic surgery; however, the differences between the treatment groups were small and not clinically relevant. Further studies are warranted to determine adverse renal effects of longer-lasting therapy with these drugs, especially in patients with renal impairment or concomitant diseases.

Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster.

Background and objective The 5% lidocaine medicated plaster is a topical treatment for peripheral neuropathic pain symptoms (e.g. burning, shooting and stabbing pain) and is registered for the treatment of postherpetic neuralgia. This study examined the efficacy and tolerability of long-term treatment with the 5% lidocaine medicated plaster in patients with localized neuropathic pain conditions. Methods Twenty patients with localized neuropathic pain [postoperative neuropathic pain (n = 14); complex regional pain syndrome (n = 2); and postherpetic neuralgia (n = 4)], who had been successfully treated with 5% lidocaine medicated plaster, were followed up by telephone interview after 3 and 5 years. Questions were related to the efficacy, development of tolerance, tolerability, wear time and comfort of the plaster. Results At 3 years, 10 out of 20 (50%) initial responders were still using the plasters with no decline in analgesic efficacy. After 5 years, eight of the original 20 responders (40%) maintained treatment and continued to experience effective pain relief. The 12 responders who discontinued treatment did so because they no longer required analgesic therapy (n = 4); their health insurer refused to fund treatment (n = 2); they were lost to follow-up (n = 1); or had died from an illness unrelated to plaster treatment (n = 5). No patient discontinued because of inadequate analgesia or intolerable side effects. Reversible erythema occurred in two patients wearing the plaster for more than 16 h. There were no systemic side effects. Conclusion The 5% lidocaine medicated plaster provides sustained pain relief over long-term treatment in patients with neuropathic pain of various causes and is well tolerated.

Cross-sectional Assessment of the Consequences of a GTP Cyclohydrolase 1 Haplotype for Specialized Tertiary Outpatient Pain Care

ObjectivesReduced-function variants of the guanosine triphosphate cyclohydrolase gene (GCH1) have been associated with reduced pain in well-defined cohorts of patients and healthy volunteers. We addressed the question whether this genetic association plays a role in outpatient pain therapy. MethodsIn a cross-sectional observational study, 523 patients were enrolled in 3 different tertiary care outpatient pain centers at German University hospitals. Of the 519 Caucasian patients, data from 424 could be analyzed for functional associations of the formerly named “pain-protective” GCH1 haplotype with the key characteristics of pain therapy being (1) actual pain, (2) opioid dosing, and (3) pain therapy duration. ResultsWith an allelic frequency of 14.2% the pain-protective haplotype was not rarer among pain patients than in the general population (P=0.344). However, a tendency toward gene dose-dependent effects of the GCH1 haplotype was observed in all the 3 therapy parameters. Carriers of the haplotype tended to have lower actual 24-hour pain scores (n=424; P=0.18), require lower opioid doses (P=0.096), and were significantly shorter on specialized pain therapy (P=0.004). The latter applied predominantly to differences between homozygous carriers and heterozygous (α-corrected t test: P=0.06) or non-carriers (P=0.011) of the haplotype. ConclusionsThe results strength the support for a modest yet reproducible and consistent pain-protective effect associated with a GCH1 haplotype known to reduce GCH1 and thus BH4 up-regulation. Pending independent verification, the results might point to a prophylactic role of decreased GCH1 up-regulation delaying the need for pain therapy.

[Pain assessment and pain treatment in the geriatric patient. Part II: pain treatment].

ZusammenfassungPrimäres Therapieziel bei geriatrischen Patienten ist der Erhalt der Funktion als Voraussetzung für Aktivität und Partizipation. Bei Patienten mit chronischen Schmerzen kann dies am besten durch einen multidisziplinären Therapieansatz unter Einschluss pharmakologischer, invasiver, bewegungstherapeutischer, pflegerischer und psychologischer Ansätze erreicht werden. Die Pharmakotherapie sollte sich wie bei jüngeren Patienten am Stufenplan der WHO orientieren und sowohl die veränderte Stoffwechsellage älterer Patienten als auch die häufig anzutreffenden Komorbiditäten berücksichtigen. Das körperliche Training sollte nach lernpsychologischen Prinzipien erfolgen und genauso wie die psychologischen Maßnahmen zur Schmerzbewältigung die Motivation zur Eigenaktivität fördern. In Kliniken und Pflegeheimen kommt den Pflegekräften die Aufgabe zu, Therapiebedarf zu erkennen und Therapieschemata umzusetzen. Da nicht alle Schmerzen wirksam behandelt werden können, wird insbesondere im terminalen Stadium die palliative Versorgung bedeutsam. Eine Sterbehilfe durch den Arzt ist in Deutschland nicht zugelassen.AbstractA primary goal of pain treatment in geriatric patients consists of maintaining physical and mental function, which is a precondition of activity and participation. In patients with chronic pain, multidisciplinary treatment without excluding invasive procedures is the most effective approach. The medication ladder, suggested by the WHO initially for cancer pain, provides a guideline for pharmacological treatment. Due to age-dependent alterations in the kinetics and dynamics of pharmaceuticals, the titration of the medication follows the rule “start low and go slow.” The same principle holds true for the maintenance or augmentation of physical activity in order to escape from the activity-deconditioning cycle. The training should be based on learning theories, include pain management strategies, and incorporate psychological approaches to facilitate the active participation of the patient in the treatment program. In hospitals and nursing homes, nurses play an important role in defining the need for pain treatment and in supervising the patient in the treatment process. Despite all these endeavors, a significant number of patients remains whose pain cannot be controlled sufficiently. Euthanasia on demand of the patient with untreatable pain is not admitted in Germany.