Eija Kalso

Pharmacologic management of neuropathic pain: evidence-based recommendations.

Abstract 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 α2‐δ 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.

Opioids in chronic non-cancer pain: systematic review of efficacy and safety

&NA; Opioids are used increasingly for chronic non‐cancer pain. Controversy exists about their effectiveness and safety with long‐term use. We analysed available randomised, placebo‐controlled trials of WHO step 3 opioids for efficacy and safety in chronic non‐cancer pain. The Oxford Pain Relief Database (1950–1994) and Medline, EMBASE and the Cochrane Library were searched until September 2003. Inclusion criteria were randomised comparisons of WHO step 3 opioids with placebo in chronic non‐cancer pain. Double‐blind studies reporting on pain intensity outcomes using validated pain scales were included. Fifteen randomised placebo‐controlled trials were included. Four investigations with 120 patients studied intravenous opioid testing. Eleven studies (1025 patients) compared oral opioids with placebo for four days to eight weeks. Six of the 15 included trials had an open label follow‐up of 6–24 months. The mean decrease in pain intensity in most studies was at least 30% with opioids and was comparable in neuropathic and musculoskeletal pain. About 80% of patients experienced at least one adverse event, with constipation (41%), nausea (32%) and somnolence (29%) being most common. Only 44% of 388 patients on open label treatments were still on opioids after therapy for between 7 and 24 months. The short‐term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients in these studies went on to long‐term management with opioids. The small number of selected patients and the short follow‐ups do not allow conclusions concerning problems such as tolerance and addiction.

A new definition of neuropathic pain

1. IntroductionIASP has recently published a new definition of neuropathic pain according to which neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system” (www.iasp-pain.org/resources/painDefinition). This definition replaces the 17-year old definition that ap

Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety.

BACKGROUND:Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain. These properties may also be beneficial in acute postoperative pain. In this study we evaluated randomized, controlled trials examining the analgesic efficacy, adverse effects, and clinical value of gabapentinoids in postoperative pain. METHODS:A systematic search of Medline, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) databases yielded 22 randomized, controlled trials on perioperative administration of gabapentinoids for postoperative pain relief. RESULTS:Pain relief was better in the gabapentin groups compared with the control groups. The opioid-sparing effect during the first 24 h after a single dose of gabapentin 300–1200 mg, administered 1–2 h preoperatively, ranged from 20% to 62%. The combined effect of a single dose of gabapentin was a reduction of opioid consumption equivalent to 30 ± 4 mg of morphine (mean ± 95% CI) during the first 24 h after surgery. Metaregression analysis suggested that the gabapentin-induced reduction in the 24-h opioid consumption was not significantly dependent on the gabapentin dose. Gabapentin reduced opioid-related adverse effects, such as nausea, vomiting, and urinary retention (number-needed-to-treat 25, 6, and 7, respectively). The most common adverse effects of the gabapentinoids were sedation and dizziness (number-needed-to-harm 35 and 12, respectively). CONCLUSIONS:Gabapentinoids effectively reduce postoperative pain, opioid consumption, and opioid-related adverse effects after surgery. Conclusions about the optimal dose and duration of the treatment cannot be made because of the heterogeneity of the trials. Studies are needed to determine the long-term benefits, if any, of perioperative gabapentinoids.

Chronic pain after thoracic surgery: a follow-up study

Background: The incidence of long‐term post‐thoracotomy pain is reported to be up to 67%. A relationship between the severity of acute postoperative pain and the development of chronic post‐thoracotomy pain has been suggested.

Pain and other symptoms during the first year after radical and conservative surgery for breast cancer

This study assessed pain, neurological symptoms, oedema of the ipsilateral arm, anxiety and depression occurring in women treated surgically for breast cancer, the impact of these symptoms on daily life and how they evolved during the 1 year follow-up. Ninety-three consecutive patients with non-metastasised breast cancer who were treated during 1993-94 were examined before surgery and after 1, 6 and 12 months. They were asked about pain, neurological symptoms and oedema in the breast scar region and/or ipsilateral arm. Sensory testing was performed, and gripping force and the circumference of the arm were measured. Anxiety and depression were evaluated. One year after surgery, 80% of the women had treatment-related symptoms in the breast scar region and virtually all patients had symptoms in the ipsilateral arm. The incidence of chronic post-treatment pain was higher after conservative surgery than after radical surgery (breast area: 33% vs 17%, NS; ipsilateral arm: 23% vs 13%, NS). Numbness occurred in 75% and oedema of the ipsilateral arm in over 30% of the patients after both radical and conservative surgery. Phantom sensations in the breast were reported by 25% of the patients. No difference in psychic morbidity was detected after the two types of surgery. Both the anxiety and depression scores were highest before surgery, decreasing with time, and were significantly correlated with preoperative stressful events.

Recommendations for using opioids in chronic non-cancer pain.

1 . The management of chronic pain should be directed by the underlying cause of the pain. Whatever the cause, the primary goal of patient care should be symptom control. 2 . Opioid treatment should be considered for both continuous neuropathic and nociceptive pain if other reasonable therapies fail to provide adequate analgesia within a reasonable timeframe. 3 . The aim of opioid treatment is to relieve pain and improve the patients quality of life. Both of these should be assessed during a trial period. 4 . The prescribing physician should be familiar with the patients psychosocial status. 5 . The use of sustained‐release opioids administered at regular intervals is recommended. 6 . Treatment should be monitored. 7 . A contract setting out the patients rights and responsibilities may help to emphasize the importance of patient involvement. 8 . Opioid treatment should not be considered a lifelong treatment.

Morphine and oxycodone hydrochloride in the management of cancer pain

In a double‐blind crossover study, morphine and oxycodone hydrochloride were administered to 20 patients who were experiencing severe cancer pain. The peroral doses were determined on the basis of patient‐controlled intravenous titration. The assumed oral bioavailability ratios were 44% (group 1, first 10 patients) and 33% (group 2, last 10 patients) for morphine and 66% (group 1) and 50% (group 2) for oxycodone hydrochloride, respectively. However, the patients were able to readjust their oral dosings. Equal analgesia was achieved with both drugs, but the intravenous dose of oxycodone hydrochloride needed was 30% higher than that of morphine. The median calculated oral/intravenous ratios giving comparable analgesia were 0.31 for morphine and 0.70 for oxycodone hydrochloride. Morphine caused more nausea than oxycodone hydrochloride and hallucinations occurred only during morphine treatment. Otherwise, there were no major differences in the side effects between these two opioids.

Controlled-release oxycodone and morphine in cancer related pain

&NA; Controlled‐release (CR) formulations of oxycodone and morphine were compared in 45 patients with chronic cancer pain. The study was started with an open‐label, randomised titration phase to achieve stable pain control for at least 48 h, followed by a double‐blind, randomised, crossover phase in two periods, 3–6 days each. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 2:3. A daily telephone contact was maintained between the patient and the investigator. The patients were asked to assess pain intensity four times a day and acceptability of therapy twice daily, and to record possible adverse effects. Pharmacodynamic evaluations were performed at the end of each double‐blind period. The patients were allowed to use escape analgesic (respective opioid as oral solution) as needed. Twenty‐seven patients were evaluable for both safety and efficacy. Pain was well‐controlled during both stable phases. When the period effect was taken into account the two opioids provided comparable analgesia. If the results of the two periods were combined, the patients consumed significantly more escape doses and the mean pain intensities were significantly greater with CR oxycodone. The total opioid consumption ratio of oxycodone to morphine was 2:3 when oxycodone was administered first, and 3:4 when oxycodone was administered after morphine. The total incidence of adverse experiences reported by the patients was similar, but significantly more vomiting occurred with morphine, whereas constipation was more common with oxycodone.

Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review

Abstract Reduction of postoperative pain by injecting opioid into the knee joint is believed to support the hypothesis of peripheral opioid receptor activation in inflammation. The study design consisted of a systematic review of randomised controlled trials (RCTs). Main outcomes were pain intensity and the use of supplementary analgesics. Efficacy of intra‐articular bupivacaine against placebo was used as an index of internal sensitivity. Evidence of efficacy was sought in both early (0–6 h after intra‐articular injection) and late (6–24 h) periods. Thirty‐six RCTs in knee surgery were found. Six had both a local anaesthetic control and placebo; four showed internal sensitivity. All four sensitive studies had at least one outcome showing efficacy of intra‐articular morphine against placebo. Six studies compared intra‐articular morphine with intravenous or intramuscular morphine or with intra‐articular saline without a bupivacaine control. Four of the six studies showed greater efficacy for intra‐articular morphine. There was no dose‐response evident. No quantitative analysis of pooled data was done. We conclude that intra‐articular morphine may have some effect in reducing postoperative pain intensity and consumption of analgesics. These studies had significant problems in design, data collection, statistical analysis and reporting. Trials of better methodological quality are needed for a conclusive answer that intra‐articular morphine is analgesic, and that any analgesia produced is clinically useful.