Giustino Varrassi

Pharmacological treatment of chronic pain – the need for CHANGE

Abstract Background: Although chronic pain affects around 20% of adults in Europe and the USA, there is substantial evidence that it is inadequately treated. In June 2009, an international group of pain specialists met in Brussels to identify the reasons for this and to achieve consensus on strategies for improving pain management. Scope: Literature on chronic pain management was reviewed, and information presented to and discussed by a panel of experts. Findings: It was agreed that guidelines are not universally accepted by those involved in pain management, and pain treatment seems to be driven mainly by tradition and personal experience. Other factors include poor communication between patients and physicians, the side effects of analgesic drugs, and limited individualisation of therapy. Difficulty in maintaining the balance between adequate pain relief and acceptable tolerability, particularly with strong opioids, can lead to the establishment of a ‘vicious circle’ that alternates between lack of efficacy and unpleasant side effects, prompting discontinuation of treatment. The medical community’s understanding of the physiological differences between nociceptive pain and neuropathic pain, which is often more severe and difficult to treat, could be improved. Increasing physicians’ knowledge of the pharmacological options available to manage these different pain mechanisms offers the promise of better treatment decisions and more widespread adoption of a multi-mechanistic approach; this could involve loosely combining two substances from different drug classes, or administering an analgesic with two different mechanisms of action. In some circumstances, a single compound capable of addressing both nociceptive and neuropathic pain is desirable. Conclusions: To improve patient outcomes, a thorough understanding of pain mechanisms, sensitisation and multi-mechanistic management is required. Universal, user-friendly educational tools are therefore required to familiarise physicians with these topics, and also to improve communication between physicians and their pain patients, so that realistic expectations of treatment can be established.

Epidural Local Anesthetic Plus Corticosteroid for the Treatment of Cervical Brachial Radicular Pain: Single Injection Versus Continuous Infusion

BackgroundEfficacy of epidural local anesthetics plus steroids for the treatment of cervicobrachial pain is uncertain. MethodsA prospective study randomized 160 patients with cervicobrachial pain resistant to conventional therapy. Patients were divided into 4 groups on the basis of the time between pain onset and treatment initiation: group A, 40 patients with pain onset 15 to 30 days; group B, 40 patients with pain from 31 to 60 days; group C, 40 patients, 61 to 180 days; and group D, 40 patients with pain >180 days. Patients of each group were randomized to receive an epidural block with bupivacaine and methylprednisolone at intervals of 4 to 5 days (Single injection) or continuous epidural bupivacaine every 6, 12, or 24 hours plus methylprednisolone every 4 to 5 days (Continuos epidural). The maximum duration of treatment (9 blocks in Single injection, and 30 days in Continuos epidural) was dependent on achieving Pain Control (PC) ≥80% [PC is defined by this formulae: (100) (VASinitial−VASfinal)/VASinitial]. Follow-up at 1 month and 6 months compared PC and the number of pain-free hours of sleep. ResultsOne hundred forty-one patients completed the study. The 4 groups had similar characteristics. At the 1-month and 6-month follow-up analysis based on the time between pain onset and treatment initiation showed that patients of group D, who received the Continuous epidural treatment, had significantly greater PC and significantly more pain-free hours of sleep compared with similar patients in Single injection. ConclusionsTherapy with continuous epidural local anesthetic and methylprednisolone provides better control of chronic cervicobrachial pain compared with Single injection. These results are discussed with respect to the possible mechanism of action of the drugs and may relate to the physiopathologic mechanisms associated with neuronal plasticity that result in chronic pain.

A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery.

We assessed the relative morphine consumption in a combined analgesic regimen (on-demand morphine plus the nonopioids propacetamol or ketorolac) after gynecologic surgery. Two hundred women randomly received two IV doses of propacetamol 2 g or ketorolac 30 mg in a double-blinded, double-dummy trial.

The impact of pain on labor force participation, absenteeism and presenteeism in the European Union

Abstract Objectives: The aims of this paper are to generate estimates of the association between the experience and burden of pain, by severity and frequency, with (1) labor force participation and workforce status in five EU countries (the UK, France, Spain, Germany and Italy) and (2) patterns of absenteeism and presenteeism for the employed workforce. Methods: Data are from the internet-based 2008 National Health and Wellness Survey (NHWS). This survey covers both those who report experiencing pain in the last month as well as the no pain population. A series of regression models are developed with the no pain group as the reference category. The impact of pain, categorized by severity and frequency reported, is assessed within a labor supply framework for (1) labor force participation and (2) absenteeism and presenteeism. In the former case both binomial and multinomial logistic models are estimated; in the latter case ordered logit models are estimated. Results: The results demonstrate that, in the context of health status, the experience of frequent severe and moderate pain has a dominant, independent and negative association with labor force participation and employment status as well as absenteeism and presenteeism. The presence of severe daily pain is associated with a 20-point reduction in the probability of being employed full-time; with moderate daily pain associated with a 10-point reduction. The impact of pain is far greater than the potential impact of other health status measures (e.g., chronic comorbidities and BMI). The experience of pain, notably severe and frequent pain, also outstrips the impact of other health status factors in absenteeism and presenteeism. Conclusions: The experience of pain, in particular severe daily pain, has a substantial negative association with labor force participation in these five European countries as well as reported absenteeism and presenteeism. As a measure of health status, it clearly outweighs other health status measures. Whether or not pain is considered as a disease in its own right, the experience of chronic pain, as defined here, presents policy makers with a major challenge. Programs to relieve the burden of pain in the community clearly have the potential for substantial benefits from societal, individual and employer perspectives.

The societal impact of pain in the European Union: health-related quality of life and healthcare resource utilization

Abstract Objectives: This paper reports on the results of a series of quantitative assessments of the association of severe and frequent pain with health-related quality of life and healthcare resource utilization in five European countries. Methods: The analysis contrasts the contribution of the increasing severity and frequency of pain reported against respondents reporting no pain in the previous month. The data are taken from the 2008 National Health and Wellness Survey. Single-equation generalized linear regression models are used to evaluate the association of pain with the physical and mental component scores of the SF-12 questionnaire as well as health utilities generated from the SF-6D. In addition, the role of pain is assessed in its association with healthcare provider visits, emergency room visits and hospitalizations. Results: The results indicate that the experience of pain, notably severe and frequent pain, is substantial and is significantly associated with the SF-12 physical component scores, health utilities and all aspects of healthcare resource utilization, which far outweighs the role of demographic and socioeconomic variables, health risk factors (in particular body mass index) and the presence of comorbidities. In the case of severe daily pain, the marginal contribution of the SF-12 physical component score is a deficit of −17.86 compared to those reporting no pain (population average score 46.49), while persons who are morbidly obese report a deficit of only −6.63 compared to those who are normal weight. The corresponding association with health utilities is equally dramatic with a severe daily pain deficit of −0.19 compared to those reporting no pain (average population utility 0.71). Conclusions: For the five largest EU countries, the societal burden of pain is considerable. The experience of pain far outweighs the contribution of more traditional explanations of HRQoL deficits as well as being the primary factor associated with increased provider visits, emergency room visits and hospitalizations.

Clonidine for treatment of postoperative pain: a dose-finding study.

The aim of this double‐blind randomized study was to evaluate the optimal intravenous dose of Clonidine administrated during the peri‐operative period, after lumbar hemilaminectomy for herniated disk repair. The ‘optimal intravenous dose’ was defined as that providing minimal analgesic request, stable haemodynamic profile and a minimal sedation score during 12 h after extubation. Eighty adult patients, ASA physical status I–II, undergoing lumbar hemilaminectomy for herniated disk (L4‐L5, L5‐S1) were included in the study. All the patients were randomly assigned to one of four study groups (A, B, C, D), 20 patients each. The same standardized general anaesthesia was performed for each group. Thirty minutes before the end of surgery, group A, B and C patients received three different loading doses of intravenous Clonidine (5 μg/kg, 3 μg/kg, 2 μg/kg respectively), followed by the same infusion of intravenous Clonidine (0.3 μg/kg per hour). Group D patients received a bolus dose and a continuous infusion of NaCl 0.9%. In the recovery unit, postoperative pain was treated by a patient‐controlled analgesia device, containing morphine. Pain relief was evaluated by the total morphine requirement during the postoperative period. Systolic blood pressure (SBP), heart rate and sedation were also noted during the first 12 h postoperatively. Intravenous Clonidine decreased morphine requirements in a dose‐dependent manner. Group A, B, C and D patients requested 5 ± 2, 11 ± 3, 19 ± 4 and 29 ± 8 doses of morphine respectively. Clonidine also affected SBP in a dose‐related manner. Group A, B and C patients had an SBP decrease respectively of 26 ± 3%, 7 ± 4% and 2 ± 2% compared with basic values while, at the same time, in group D patients no SBP variation was registered. In conclusion, this study demonstrates that, when sedation and analgesic effect of Clonidine is required, 3 μg/kg bolus dose followed by a continuous infusion of 0.3 μg/kg per hour has to be considered the optimal intravenous dose. The higher dose of intravenous Clonidine (5 μg/kg) produced better analgesia but the degree of hypotension and sedation was more severe and longer lasting; it required ephedrine administration and careful monitoring of the patient. On the other hand, the bolus of intravenous Clonidine 2 μg/kg (group C) was less effective in terms of pain relief but with similar side‐effects to the 3 μg/kg dosage (group B).

The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment

Abstract Chronic pain is currently under-diagnosed and under-treated, partly because doctors’ training in pain management is often inadequate. This situation looks certain to become worse with the rapidly increasing elderly population unless there is a wider adoption of best pain management practice. This paper reviews current knowledge of the development of chronic pain and the multidisciplinary team approach to pain therapy. The individual topics covered include nociceptive and neuropathic pain, peripheral sensitization, central sensitization, the definition and diagnosis of chronic pain, the biopsychosocial model of pain and the multidisciplinary approach to pain management. This last section includes an example of the implementation of a multidisciplinary approach in Belgium and describes the various benefits it offers; for example, the early multidimensional diagnosis of chronic pain and rapid initiation of evidence-based therapy based on an individual treatment plan. The patient also receives continuity of care, while pain relief is accompanied by improvements in physical functioning, quality of life and emotional stress. Other benefits include decreases in catastrophizing, self-reported patient disability, and depression. Improved training in pain management is clearly needed, starting with the undergraduate medical curriculum, and this review is intended to encourage further study by those who manage patients with chronic pain.

Which induction drug for cesarean section? a comparison of thiopental sodium, propofol, and midazolam

STUDY OBJECTIVE To determine maternal and neonatal effects of three different induction drugs (thiopental sodium, propofol, and midazolam) for cesarean section. DESIGN Randomized, double-blind study. SETTING Inpatient obstetric department at a general hospital. PATIENTS 90 healthy patients undergoing elective cesarean section with general anesthesia. INTERVENTIONS 3 groups of 30 patients each receiving thiopental 5 mg/kg, propofol 2.4 mg/kg, or midazolam 0.3 mg/kg for induction of anesthesia. MEASUREMENTS AND MAIN RESULTS Time to induce anesthesia, hemodynamic changes, depth of anesthesia, recovery after anesthesia, placental transfer, and neonatal outcome (Apgar and neurobehavioral examinations) were studied. In the thiopental and midazolam groups, systolic blood pressure and heart rate rose following endotracheal intubation and skin incision (p < 0.001 and p < 0.0025, respectively), while in the propofol group, there was significant hypotension after induction (p < 0.005). Electroencephalographic patterns showed a light depth of anesthesia with propofol and midazolam between anesthesia induction and delivery, confirmed by the presence of clinical signs of light anesthesia in 50% of propofol patients and 43% of midazolam patients. Time to induce anesthesia was longer with midazolam (p < 0.0001). Neonates in the midazolam and propofol groups had lower Apgar and neurobehavioral scores than those in the thiopental group. Umbilical artery to umbilical vein ratios were above 1 in the propofol and midazolam groups. CONCLUSION Thiopental still remains the first-choice induction drug for cesarean section. The slow induction time with midazolam may put the mother at risk for pulmonary inhalation. A plane of anesthesia that may risk awareness and potential neonatal depression is the main drawback of the two newer induction drugs.

Intrathecal Therapy: What Has Changed With the Introduction of Ziconotide

Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national‐level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non‐opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.

The effects of perioperative ketorolac infusion on postoperative pain and endocrine-metabolic response.

We designed a randomized, double-blind study to assess the analgesic efficacy and safety of perioperative ketorolac infusion in 95 patients undergoing cholecystectomy. The ketorolac group (n = 48) received premedication, combined with ketorolac 30 mg intramuscularly (IM), followed by a ketorolac continuous infusion (2 mg/h). The control group (n = 47) received an IM bolus of NaCl 0.9% (1 mL) followed by continuous saline infusion (2 mL/h) for 24 h. Operative blood losses, postoperative pain, sedation, and on-demand morphine consumption (patient-controlled analgesia [PCA]) were measured. The effects on plasma catecholamines, cortisol, potassium, creatinine, skin bleeding time, prothrombin time (PT), and partial thromboplastin time (PTT) were also evaluated. Ketorolac improved pain scores (P < 0.05) and reduced plasma cortisol concentrations between 2 and 6 h (P < 0.05). No significant differences were observed concerning operative blood losses, glucose concentration, and renal and hemostatic functions. The ketorolac group required less morphine (not significant [NS]) than the control group and had less adverse effects (P = 0.002). Thus, perioperative ketorolac infusion improved the quality of postoperative pain relief, and had no major influence on endocrine-metabolic response and no negative influences on hemostatic and renal functions. This study suggests that preventive ketorolac administration, followed by a continuous infusion, is an easy, useful, and safe method for pain control after abdominal surgery.