Risk factors and outcomes of chronic opioid use following trauma.

BACKGROUND: The growing problem of opioid misuse has become a serious crisis in many countries. The role of trauma as a gateway to opioid use is currently not determined. The study was undertaken to assess whether traumatic injury might be associated with chronic opioid use and accompanying increased long-term mortality. METHODS: Injured patients and controls from Sweden were matched for age, sex and municipality. After linkage to Swedish health registers, opioid consumption was assessed before and after trauma. Among injured patients, logistic regression was used to investigate factors associated with chronic opioid use, assessed by at least one written and dispensed prescription in the second quarter after trauma. Cox regression was employed to study excess risk of mortality. In addition, causes of death for postinjury opioid users were explored. RESULTS: Some 13 309 injured patients and 70 621 controls were analysed. Exposure to trauma was independently associated with chronic opioid use (odds ratio 3·28, 95 per cent c.i. 3·02 to 3·55); this use was associated with age, low level of education, somatic co-morbidity, psychiatric co-morbidity, pretrauma opioid use and severe injury. The adjusted hazard ratio for death from any cause 6-18 months after trauma for chronic opioid users was 1·82 (95 per cent c.i. 1·34 to 2·48). Findings were similar in a subset of injured patients with no pretrauma opioid exposure. CONCLUSION: Traumatic injury was associated with chronic opioid use. These patients have an excess risk of death in the 6-18 months after trauma.

ANTECEDENTES: El uso indebido de opioides es un problema creciente que se ha convertido en una grave crisis en muchos países. No se ha analizado el papel de las lesiones traumáticas como puerta de entrada al uso de opioides. Se estableció la hipótesis de que una lesión traumática podría asociarse con el uso crónico de opioides y acompañarse de un aumento de la mortalidad a largo plazo. MÉTODOS: Se ajustaron por edad, sexo y municipio a los pacientes suecos con lesiones traumáticas y sus controles. Después de vincular varios registros de salud suecos, se evaluó el consumo de opioides antes y después de la lesión traumática. En los pacientes con lesiones traumáticas, se utilizó una regresión logística para definir los factores asociados con el uso crónico de opioides, definida como una receta prescrita y dispensada en el segundo trimestre después de la lesión traumática, y ​​una regresión de Cox para estudiar el exceso de riesgo de mortalidad. Además, se exploraron las causas de muerte de los usuarios de opioides postraumáticos. RESULTADOS: Se analizaron 13.309 pacientes con lesiones traumáticas y 70.621 controles. La exposición a una lesión traumática se asoció de forma independiente con el uso crónico de opioides, (razón de oportunidades, odds ratio, OR) OR 3,3 (i.c. del 95% 3,0-3,6), y dicho uso se asoció con la edad, el bajo nivel educativo, las comorbilidad físicas y psiquiátricas, el uso previo de opioides y la gravedad de las lesiones. El cociente de riesgos instantáneos, hazard ratio, HR ajustado de muerte por cualquier causa a los 6-18 meses de la lesión traumática para los consumidores crónicos de opioides fue de 1,8 (i.c. del 95% 1,3-2,5). En un subconjunto de pacientes con lesiones traumáticas sin exposición previa a los opioides, los hallazgos fueron similares. CONCLUSIÓN: La lesión traumática se asoció con el uso crónico de opioides. Estos pacientes presentan un exceso de riesgo de mortalidad entre los 6 y 8 meses después del trauma.

Socio-economic burden of patients with a diagnosis related to chronic pain--register data of 840,000 Swedish patients.

BACKGROUND: Chronic pain constitutes a substantial socio-economic challenge but little is known about its actual cost. AIM: To estimate the direct and indirect costs of patients with a diagnosis related to chronic pain (DRCP), to determine variation in these costs across different diagnosis groups, and to identify what resources constitute the most important components of costs. METHODS: Patient level data from three administrative registries in Västra Götalandsregionen in Sweden including inpatient and outpatient care, prescriptions, long-term sick-leaves, and early retirement were extracted. Patients with a DRCP between January 2004 and November 2009 were selected. RESULTS: In total, 840,000 patients with a DRCP were identified. The mean total costs per patient and year were estimated at 6400 EUR but were higher for patients with cancer (10,400 EUR). Patients on analgesic drugs had more than twice as high costs as patients without analgesic drugs, on average. Indirect costs (sick-leaves and early retirement) constituted the largest cost component (59%) followed by outpatient (21%) and inpatient care (14%), whereas analgesic drug prescriptions constituted less than 1 percent of the total. CONCLUSIONS: The socio-economic burden of patients with a diagnosis related to chronic pain amounts to 32 billion EUR per year, when findings from Västra Götalandsregionen are extrapolated to the whole of Sweden. This compares to a fifth of the total Swedish tax burden in 2007 or about a tenth of Swedish GDP. This study does not provide evidence on what costs are caused by chronic pain per se. However, the higher costs of patients on analgesic drugs might indicate that the consequences of pain are of major importance.

Procedure-related pain among adult patients with hematologic malignancies.

BACKGROUND: Cancer patients undergo numerous invasive diagnostic procedures. However, there are only sparse data on the characteristics and determinants for procedure-related pain among adult cancer patients. METHODS: In this prospective study, we evaluated the characteristics and determinants of procedure-related pain in 235 consecutive hematologic patients (M/F:126/109; median age 62 years, range 20-89 years) undergoing a bone marrow aspiration/biopsy (BMA) under local anesthesia. Questionnaires were used to assess patients before-, 10 min and 1-7 days post BMA. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: 165/235 (70%) patients reported pain during BMA; 92 (56%), 53 (32%) and 5 (3%) of these indicated moderate [visual analogue scale (VAS)>or=30 mm], severe (VAS>54 mm) and worst possible pain (VAS=100 mm), respectively. On multivariate analyses, pre-existing pain (OR=2.60 95% CI 1.26-5.36), anxiety about the diagnostic outcome of BMA (OR=3.17 95% CI 1.54-6.52), anxiety about needle-insertion (OR=2.49 95% CI 1.22-5.10) and low employment status (sick-leave/unemployed) (OR=3.14 95% CI 1.31-7.55) were independently associated with an increased risk of pain during BMA. At follow-up 10 min after BMA, 40/235 (17%) patients reported pain. At 1, 3, 6 and 7 days post BMA, pain was present in 137 (64%), 90 (42%), 43 (20%) and 25 (12%) patients, respectively. CONCLUSIONS: We found that 3/4 of hematologic patients who underwent BMA reported procedural pain; one third of these patients indicated severe pain. Pre-existing pain, anxiety about the diagnostic outcome of BMA or needle-insertion, and low employment status were independent risk factors.

Systemic adenosine infusion reduces the area of tactile allodynia in neuropathic pain following peripheral nerve injury: a multi-centre, placebo-controlled study.

Systemic adenosine has been shown in earlier case reports and a small placebo-controlled study to reduce pathological sensory dysfunction such as tactile allodynia in neuropathic pain. To evaluate this further, the effects of systemic adenosine infusion (50 microg/kg/min for 60 min) on tactile sensory dysfunction and pain was evaluated in 26 patients suffering peripheral neuropathic pain characterized by dynamic tactile allodynia. A randomized, cross-over, double-blind, placebo-controlled technique was used in this multi-centre study. Psychophysical methods were used to evaluate sensory dysfunction and spontaneous pain. The area of dynamic tactile allodynia was significantly reduced by adenosine compared with placebo (p=0.043), but spontaneous pain and tactile pain threshold were not significantly improved compared with the effects of placebo treatment. As a secondary outcome, a higher incidence of positive subjective effects on the clinical pain condition, in a few cases with long duration (several months), following adenosine treatment was found when the global effect of respective treatment was assessed (p=0.028). The results demonstrate involvement of adenosine receptor-sensitive pain mechanisms in some aspects of the sensory dysfunction often found in neuropathic pain.

Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain.

UNLABELLED: Secondary hyperalgesia is characterized by increased sensitivity to noxious mechanical stimuli in the area surrounding injured skin. The pathophysiological mechanisms involve increased excitability of second-order neurons located in the spinal cord, i.e., central sensitization. The mechanisms behind this phenomenon may be of importance in clinical pain, including neuropathic pain. To study the effects of systemic infusion of the endogenous compound adenosine (ADO) on sensory function, a superficial cutaneous burn injury was induced by the 4-min topical application of mustard oil or by heat (47 degrees C for 7 min) during i.v. ADO infusion (60 microg x kg(-1) x min(-1)). Healthy human subjects (n = 10 for each model) were tested, using a blinded, placebo-controlled procedure. The area of secondary hyperalgesia, as well as tactile and thermal sensory function, was tested using psychophysical methods during and after treatments. ADO significantly reduced the area of secondary hyperalgesia in both models. The maximal reduction compared with placebo was 58% +/- 20% (heat burn) and 39% +/- 13% (mustard oil burn). No other differences in sensory function were observed. The results are interpreted as an ADO-induced modulatory effect on the mechanisms of central sensitization. IMPLICATIONS: We tested the effects of adenosine on the development of increased sensitivity in the skin surrounding a superficial skin injury in humans. A superficial skin bum was induced with a chemical irritant or heat. The results show that adenosine reduces the skin area with increased sensitivity surrounding the injury.

Intrathecal administration of the adenosine A1 receptor agonist R-phenylisopropyl adenosine reduces presumed pain behaviour in a rat model of central pain.

Effects of intrathecally (i.t.) administered R-phenylisopropyl adenosine (R-PIA), an adenosine A1 receptor agonist, on presumed pain behaviour were assessed in a rat model of chronic central pain. Spinal cord injury was induced photochemically via laser irradiation of the spinal cord after intravenous injection of erythrosin B in rats. The chronic allodynia-like behaviour that developed in some animals was studied. R-PIA (3 and 10 nmol), injected i.t. reduced the mechanical and cold allodynia-like symptoms as tested with von Frey filaments and ethyl-chloride spray, respectively. No side effects were observed. The effect of R-PIA was significant for up to 5 h and was reversed by theophylline, an adenosine receptor antagonist.

Intrathecal adenosine analog administration reduces substance P in cerebrospinal fluid along with behavioral effects that suggest antinociception in rats.

UNLABELLED: Adenosine and adenosine analogs induce analgesia in humans and presumed antinociception in animal models when administered both systemically and intrathecally. In the present investigation in rats, we studied the effects of intrathecally administered adenosine analogs, with or without systemic coadministration of an adenosine antagonist (theophylline), on substance P (SP) and calcitonin gene-related peptide (CGRP) concentrations in cerebrospinal fluid (CSF). In parallel, nociceptive reflex testing (tail immersion latency) and motor function were evaluated. The potent unselective adenosine receptor agonist N-ethylcarboxamide-adenosine (NECA) and the relatively adenosine A1 receptor selective agonist R-phenyl-isopropyl-adenosine (R-PIA) both reduced SP-like immunoreactivity (-LI) by 50%, whereas CGRP-LI remained unchanged. There was a dose-dependent increase in tail immersion latency. This effect was present without motor impairment when R-PIA was administered in doses up to 5 nmol. R-PIA (10-100 nmol), as well as 1-100 nmol of the unselective agonist NECA, produced dose-dependent motor impairment. The reduction of SP-LI as well as the behavioral effects were reversed by theophylline. We conclude that SP reduction in CSF, which possibly reflects reduced SP turnover after adenosine receptor stimulation, provides an additional possible mechanism of action for the analgesic effects of adenosine. IMPLICATIONS: We studied the interactions between the known pain mediator substance P and substances with effects similar to the endogenous pain modulator adenosine in rats. The results suggest that the pain-reducing effect of adenosine is, at least partly, due to a reduction of substance P in cerebrospinal fluid.

Intrathecal and systemic R-phenylisopropyl-adenosine reduces scratching behaviour in a rat mononeuropathy model.

The aim of the present study was to investigate the effect of intravenous or intrathecal (i.t.) administration of R-phenylisopropyladenosine (R-PIA), a selective A1 adenosine receptor agonist, on spontaneous scratching behaviour, a phenomenon presumably related to pain in a mononeuropathy model (sciatic nerve ligation) in rats. The acute effect of daily i.t. R-PIA injections was studied up to 21 days following nerve ligation. The results demonstrate that both i.v. (30 nmol) and i.t. (3 nmol) R-PIA, in doses not producing any motor impairment, significantly reduces scratching behaviour in this animal model. The mechanism of action for this presumed antinociceptive effect is suggested to occur at the spinal cord level.

Systemic adenosine infusion alleviates spontaneous and stimulus evoked pain in patients with peripheral neuropathic pain.

In seven patients with peripheral neuropathic pain, the effect of systemic adenosine infusion on pain symptoms was evaluated in a double-blind, placebo controlled, cross-over study. The study infusions, adenosine (50 micrograms.kg-1.min-1) or placebo, were given intravenously (IV) during 45-60 min at two separate occasions. Before and during infusions, bedside examination of sensibility and quantitative sensory testing (QST), i.e., assessments of perception thresholds for touch, touch-evoked pain, cold, warmth, painful heat, and cold, were performed. In the neuropathic area, sensation magnitude was rated by a visual analog scale (100 mm VAS) using a pin and at perception threshold for touch-evoked pain using von Frey filaments. Adenosine infusion reduced spontaneous pain (P < 0.05), and caused an increase of the touch-evoked pain threshold from 10.8 +/- 5.3 to 22.2 +/- 6.9 g (P < 0.05), whereas placebo had no effect. Pain intensity at perception threshold for touch-evoked pain was, however, unaltered. Pinprick-evoked pain in the neuropathic areas was reduced from 53 +/- 11 to 29 +/- 10 mm (P < 0.05). No other sensory modality was consistently changed during adenosine infusion. In conclusion, the present study demonstrates that adenosine infusion alleviates spontaneous neuropathic pain, tactile allodynia, and pinprick hyperalgesia in patients with peripheral neuropathic disorders, probably by a central mechanism of action.

Systemic adenosine attenuates touch evoked allodynia induced by mustard oil in humans.

The effect of adenosine on tactile allodynia (secondary hyperalgesia) was studied in 6 healthy volunteers, using a double-blind, placebo controlled, cross-over design. Tactile allodynia was induced by topical application of mustard oil on the skin of the volar aspect of the forearm. Adenosine (50 micrograms kg-1 min-1) or saline was given intravenously for 20 min before the mustard oil application and continued for another 50 min. The tactile allodynic areas for brush and von Frey filament stimulation were both significantly reduced by approximately 50% during adenosine infusion, compared with placebo. The threshold for eliciting allodynia with von Frey filaments was not influenced by adenosine. The study shows that adenosine can reduce the area of mustard oil induced tactile allodynia.