Paracetamol + tramadol: new preparation. No advance

(1) First-line treatment for both acute and chronic pain is paracetamol or, if necessary, ibuprofen, a nonsteroidal antiinflammatory drug. If relief is inadequate, the best option is a combination of paracetamol with codeine (a weak opiate). (2) A fixed-dose combination of paracetamol (325 mg) and tramadol (37.5 mg), a weak opiate, arrived on the French market in May 2003. (3) In the acute setting, three trials in a total of 1197 patients showed that a single dose of the paracetamol 650 mg + tramadol 75 mg combination after dental surgery was no more effective than ibuprofen 400 mg. Compared with each drug used alone, the paracetamol + tramadol combination prolongs the analgesic effect but does not increase its intensity. (4) A trial after gynaecological surgery and another trial after orthopaedic surgery showed that a single dose of paracetamol 975 mg + tramadol 112.5 mg had similar efficacy to tramadol alone at 112.5 mg. (5) In the chronic setting, we found no trials comparing the paracetamol + tramadol combination with each drug used alone. A comparative double-blind trial in 462 patients with low back pain or osteoarthritic pain showed no difference in efficacy between paracetamol 325 mg + tramadol 37.5 mg and paracetamol 300 mg + codeine 30 mg. (6) The main adverse effects of the paracetamol + tramadol combination are the same as other weak opiates: nausea, vomiting, dizziness, headache, drowsiness and constipation. Tramadol carries a higher risk of drug interactions than codeine. (7) In practice, the paracetamol + tramadol combination offers patients no advantages relative to standard analgesics.     

Pharmacological treatments for persistent non-malignant pain in older persons

Persistent non-malignant pain is common, often neglected and under-treated among older persons. Some older adults do not complain because they consider chronic pain to be a characteristic of normal aging. Physicians have concerns regarding adverse effects of pharmacological treatment. The model of the World Health Organization for treatment of cancer pain is generally accepted and also recommended for persistent non-cancer pain. Furthermore, non-pharmacological treatment should complement drug treatment whenever possible. An initial assessment and possible treatment of underlying causes of pain are pertinent. Modern pharmacological pain management is based on non-opioid and opioid analgesics. NSAIDs are among the most widely prescribed class of drugs in the world. The new cyclo-oxygenase-2 inhibitors such as celecoxib and rofecoxib offer an alternative for the treatment of mild-to-moderate pain in patients with a history of gastric ulcers or bleeding. Paracetamol (acetaminophen) is being used widely for the management of mild pain across all age groups as it has moderate adverse effects at therapeutic dosages. For moderate pain, a combination of non-opioid analgesics and opioid analgesics with moderate pain relief properties (e.g. oxycodone, codeine, tramadol and tilidine/naloxone) is recommended. For severe pain, a combination of non-opioid analgesics and opioid analgesics with strong pain relief properties (e.g. morphine, codeine) is recommended. The least toxic means of achieving systemic pain relief should be used. For continuous pain, sustained-release analgesic preparations are recommended. Drugs should be given on a fixed time schedule, and possible adverse effects and interactions should be carefully monitored. Adjuvant drugs, such as antidepressants or anticonvulsants, can be very effective especially in the treatment of certain types of pain, such as in diabetic neuropathy. Effective pain management should result in decreased pain, increased function and improvement in mood and sleep.     

Characteristics of methadone maintenance treatment patients prescribed opioid analgesics

ABSTRACT

Background: Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them with MMT patients not prescribed opioid analgesics. Methods: We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012 to 2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients' report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-square tests, t tests, and Mann-Whitney U tests. Results: Of 611 MMT patients, most reported chronic pain (62.0%), hepatitis C virus (HCV) infection (52.1%), and current use of illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 1.1–2.3) and chronic pain (aOR = 7.6, 95% CI: 4.6–12.6). Conclusion: Among MMT patients primarily in 3 Bronx clinics, nearly one third reported taking prescribed opioid analgesics. Compared with patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients.     

Opioid receptor targeting ligands for pain management: a review and update

Importance of the field: Discovery and synthesis of analgesic ligands can potentially improve analgesia, reduce side effects, minimize psychologic dependence and delay analgesic tolerance. Areas covered in this review: This review covers opioid peptides and analogs and bifunctional opioid ligands, and bifunctional opioid/non-opioid ligands as new, potentially useful analgesics. Several lines of investigation have resulted in potentially useful agents. What the reader will gain: Modifications of peptide structures have improved opioid receptor affinity, efficacy, stability, half-life and CNS penetrations. Opioid μ receptor agonists have been used to form multi-targeted directed ligands (MDL), which in animal models improve the therapeutic index of the analgesic relative to monovalent potent μ receptor agents. These new opioid ligands are reviewed in detail. Take home message: Modified opioid peptides and MDL ligands are potentially better analgesics than morphine.     

Perioperative pain management

The under-treatment of postoperative pain has been recognised to delay patient recovery and discharge from hospital. Despite recognition of the importance of effective pain control, up to 70% of patients still complain of moderate to severe pain postoperatively.The mechanistic approach to pain management, based on current understanding of the peripheral and central mechanisms involved in nociceptive transmission, provides newer options for clinicians to manage pain effectively. In this article we review the rationale for a multimodal approach with combinations of analgesics from different classes and different sites of analgesic administration. The pharmacological options of commonly used analgesics, such as opioids, NSAIDs, paracetamol, tramadol and other non-opioid analgesics, and their combinations is discussed. These analgesics have been shown to provide effective pain relief and their combinations demonstrate a reduction in opioid consumption.The basis for using non-opioid analgesic adjuvants is to reduce opioid consumption and consequently alleviate opioid-related adverse effects. We review the evidence on the opioid-sparing effect of ketamine, clonidine, gabapentin and other novel analgesics in perioperative pain management. Most available data support the addition of these adjuvants to routine analgesic techniques to reduce the need for opioids and improve quality of analgesia by their synergistic effect. Local anaesthetic infiltration, epidural and other regional techniques are also used successfully to enhance perioperative analgesia after a variety of surgical procedures. The use of continuous perineural techniques that offer prolonged analgesia with local anaesthetic infusion has been extended to the care of patients beyond hospital discharge.The use of nonpharmacological options such as acupuncture, relaxation, music therapy, hypnosis and transcutaneous nerve stimulation as adjuvants to conventional analgesia should be considered and incorporated to achieve an effective and successful perioperative pain management regimen.     

Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non‐opioid analgesics, namely nefopam, a centrally acting non‐opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo‐oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED₅₀ values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED₅₀ values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of nefopam at a non‐analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan‐induced tactile allodynia, the combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non‐analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.     

Reasons for the use of mild analgesics among English students

Objective Mild analgesics such as paracetamol and ibuprofen are amongst the most commonly used over-the-counter (OTC) drugs. However, little is known about what beliefs people hold about them. The present paper examines: (a) the patterns of mild analgesic usage in a sample of university students, (b) their beliefs about the associated risks and the necessity of taking mild analgesics, and (c) the association between beliefs about analgesics and self-reports of their use. Setting A convenience sample of 333 students studying at a large English University were approached on the University campus. Of these, 291 agreed to participate, yielding an 87% response rate. Method This study employed a cross-sectional design, with all participants completing the same questionnaire concerning their use of mild painkillers, such as paracetamol and ibuprofen, and beliefs about their use. Main outcome measure Four questions asked about their patterns of mild analgesic use in the past month, specifically (a) have they taken analgesics, (b) how often did they take analgesics when they had symptoms, (c) did they take more than a single dose of 1–2 tablets at one time, and (d) did they exceed the maximum dose. Results Almost all of the 291 participants reported symptoms in the past month, with over two thirds treating with mild analgesics, and one sixth exceeding the maximum dose. Only 17% indicated that there were short-term risks of using mild analgesics, although half indicated that there were long-term risks. The risks that were identified generally did not conform with current medical thinking. Perceptions of risks were not generally associated with self-reports of analgesic usage. Rather, respondents who thought analgesics were more necessary were more likely to report taking analgesics, report taking more analgesics, and report exceeding the maximum dose. Conclusion These results indicate the need for caution in current moves to encourage self-medication. If people are unaware of the risks of drugs such as paracetamol or ibuprofen, then they may only contact health professionals after they experience adverse effects     

A comparison of four analgesics in post-episiotomy pain

This study was conducted to compare the analgesic efficacy of four commonly used analgesics namely ibuprofen, analgin, paracetamol and aspirin in post-episiotomy pain. The subjects were healthy postpartum women on the obstetric service of Goa Medical College, each of whom received only one experimental medication. Subjective reports were used as indices of pain intensity or relief. Ibuprofen was found to be the most effective analgesic in post-episiotomy pain followed by analgin and paracetamol in that order. Surprisingly, aspirin was found to be no better than placebo.     

Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain

BACKGROUND AND PURPOSE: The analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX-1, COX-2) but more potent on COX-3. Both are also weak anti-inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms.EXPERIMENTAL APPROACH: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 microg lambda-carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG. KEY RESULTS: Pretreatment with paracetamol or dipyrone (60-360 mg kg(-1)) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non-inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone-induced analgesia.CONCLUSIONS AND IMPLICATIONS: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established.     

Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain

Chronic pain is a debilitating condition that is associated with many common diseases; this places a major burden on the healthcare system. There are currently numerous analgesic agents available for the treatment of chronic pain. In general, the oral non-opioid analgesic, paracetamol, is recommended for the initial treatment of mild to moderate pain. Therapeutic doses of paracetamol do not appear to result in hepatotoxicity, although overdose may lead to acute liver failure. Current data suggest that paracetamol has acceptable gastrointestinal tolerability. Another class of non-opioid analgesic with confirmed efficacy for the treatment of chronic mild to moderate pain are non-steroidal anti-inflammatory drugs (NSAIDs), although this efficacy is offset by the potential of adverse gastrointestinal events. In particular, non-selective NSAIDs, also known as cyclooxygenase (COX) inhibitors, carry an increased risk of serious upper gastrointestinal complications, including ulcers, perforation and bleeding. The introduction of COX-2 inhibitors provided a NSAID-based option with improved gastrointestinal safety, but increased risk of cardiovascular effects. Opioids are powerful analgesic agents used to treat moderate to severe chronic pain. However, treatment with opioids is associated with a number of common adverse effects, including constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention. Although there are multiple strategies in place to manage adverse events that arise from both non-opioid and opioid analgesic therapy, a better understanding of the mechanisms involved in the development of specific drug-related adverse effects is required along with proper prescribing practices and adequate physician/patient education. Balanced against the adverse effects of pain management medications, there is a need to be mindful of the widespread, often serious, adverse consequences of poorly managed pain itself.     

Opioid receptor targeting ligands for pain management: a review and update

Importance of the field: Discovery and synthesis of analgesic ligands can potentially improve analgesia, reduce side effects, minimize psychologic dependence and delay analgesic tolerance.

Areas covered in this review: This review covers opioid peptides and analogs and bifunctional opioid ligands, and bifunctional opioid/non-opioid ligands as new, potentially useful analgesics. Several lines of investigation have resulted in potentially useful agents.

What the reader will gain: Modifications of peptide structures have improved opioid receptor affinity, efficacy, stability, half-life and CNS penetrations. Opioid μ receptor agonists have been used to form multi-targeted directed ligands (MDL), which in animal models improve the therapeutic index of the analgesic relative to monovalent potent μ receptor agents. These new opioid ligands are reviewed in detail.

Take home message: Modified opioid peptides and MDL ligands are potentially better analgesics than morphine.