Massimo Mammucari

Italian Oncological Pain Survey (IOPS) A Multicentre Italian Study of Breakthrough Pain Performed in Different Settings

Objective:A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC). Methods:A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings. Results:1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs. Conclusion:This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient’s quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics.

Adequacy assessment of oxycodone/paracetamol (acetaminophen) in multimodal chronic pain: A prospective observational study

AbstractBackground: Multimodal pain is comprised of nociceptive/inflammatory and neuropathic components. Pharmacological pain therapies from different classes provide pain relief using different mechanistic actions; often a combination of such therapies provides more effective pain relief than monotherapy. To assess whether pain management is adequate requires a comprehensive pain scoring system. Objective: To evaluate the adequacy of a low-dose combination of oxycodone and paracetamol (acetaminophen) in patients with multimodal, chronic, non-malignant pain using the Pain Management Index (PMI). Methods: During this prospective, observational study, consecutive patients were classified according to the presence of prevalent osteoarticular pain (group A, n = 78) or prevalent neuropathic pain (group B, n = 72). Existing pain-relief medications were discontinued and both groups received oxycodone 5 mg and paracetamol 325 mg up to 8 hourly for a planned duration of ≥6 weeks. Patients in group B who were receiving gabapentin continued this treatment up to a maximum daily dosage of 2400 mg during the observation period. Pain intensity was evaluated using a visual analogue scale (VAS from 0 to 10). Functional limitation for patients in group A was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The intensities of dynamic allodynia and hyperalgesia in patients in group B were evaluated by a VAS. Results from the WOMAC, dynamic allodynia, and hyperalgesia assessments were evaluated using the PMI. Results: In group A, 64.3% of patients showed improvements in pain symptoms after 15 days of treatment in the WOMAC categories of “pain preventing sleep” and “walks with aid”. The PMI showed that the oxycodone/paracetamol therapy was adequate in patients with osteoarticular pain. In group B, 83.3% of patients reported improvement in the category of “pain preventing sleep”, and all patients rated the remaining four categories (“spontaneous pain”, “burning pain”, “painful paresthesia”, and “pinprick”) as either stable or improved after 15 days of treatment. Using the PMI, hyperalgesia resolved with oxycodone/paracetamol therapy. 37.1% and 58.3% of patients did not complete the study in group A and B, respectively. Conclusion: The PMI was an effective tool for assessment of pain management efficacy. Oxycodone/paracetamol improved pain symptoms in the majority of compliant patients. In patients with neuropathic pain, rescue therapy with oxycodone/paracetamol showed a lesser, but significant, improvement of pain symptoms.

Role of Mesotherapy in Musculoskeletal Pain: Opinions from the Italian Society of Mesotherapy

Mesotherapy is the injection of active substances into the surface layer of the skin. This method allows a slower spread, higher levels, and longer lasting effects of drugs in the tissues underlying the site of injection (skin, muscle, and joint) compared with those following intramuscular injection. This technique is useful when a local pharmacological effect is required and relatively high doses of drug in the systemic circulation are not. Mesotherapy should only be undertaken following a complete clinical workup and subsequent diagnosis. Encouraging results have been reported in randomized, controlled clinical trials and in observational studies involving patients with various forms of musculoskeletal pain. Recommendations by experts from the Italian Society of Mesotherapy for appropriate use of mesotherapy in musculoskeletal pain and an algorithm for treating localized painful conditions are provided.

Breakthrough Pain in Patients Referred to Pain Clinics: The Italian Pain Network Retrospective Study

IntroductionDespite breakthrough pain (BTP) being one of the most severe forms of pain, there are no definitive data on its prevalence.MethodsThe authors performed a retrospective survey of the prevalence of BTP in consecutive patients in four Italian pain clinics, subsequent to application of an Italian law mandating detailed clinical records on pain characteristics, treatment, and results. Mean pain intensity was assessed with a numerical rating scale from 0 to 10.ResultsThe authors analyzed records of 1,401 patients (58% women, 33.1% patients with cancer). Transient episodes of severe pain or BTP were referred by 790 patients (56.4%), including 58.2% of the men (342 of 588) and 55.1% of the women (448 of 813). Among the 464 patients with cancer, 70.3% reported daily exacerbation of pain. The mean BTP intensity was 8.31 ± 1.58 and 31.1% of patients reported experiencing three episodes per day.ConclusionDespite some limitations of the study, the authors show that transient episodes of severe pain or BTP are significantly present both in cancer and other diseases, and that many patients are not yet receiving appropriate opioid therapy. The authors need validated tools at international level for the diagnosis and treatment of BTP in patients with cancer and for transitory and patients with severe non-cancer pain. A survey at national level is needed to estimate the prevalence of BTP in different settings, to plan specific medical education.

Standard Therapy with Opioids in Chronic Pain Management

AbstractObjective: Moderate to severe pain is commonly experienced by cancer and non-cancer patients. Although opioids are generally the most important drugs in chronic pain management, their use in Italy remains low. We designed a prospective open trial to assess the efficacy and safety of a standard therapy clinically available for a large range of patients. Methods: A total of 172 consecutive patients (89 women and 83 men) with chronic pain (daily mean visual analogue scale (VAS) score > 4) that was not adequately managed by their existing pain regimen were enrolled to receive an immediate release (IR) dose of morphine: 30 mg/day (opioid-naive patients) or 60 mg/day (non-naive patients) for 5 days. After this period (start therapy), all patients were switched to slow release (SR) opioid therapy for 30 days (steady therapy). Each breakthrough pain (BTP) episode was treated with a single dose of IR morphine (20% of the daily dose) during all study periods. Results: Daily VAS score was reduced from 7.4 ± 1.3 at baseline to 3.8 ± 1.5 (p < 0.0001) after 30 days of steady therapy in cancer and non-cancer patients. Fewer patients reported BTP events by study end (55% of patients with BTP at basal time had no BTP at last follow up), and the number of daily BTP events experienced by patients was reduced by therapy to 1–2 per day in 75% of patients reporting BTP. Further, the time delay to reach pain relief following administration of a rescue dose of IR morphine was 15 minutes or less in 52.1% of patients at study end. The standard therapy was well tolerated and fewer adverse effects were recorded at the end of the study period compared with baseline, with the exception of constipation, which showed a moderate increase (from 18.2% to 25.0%). Conclusion: Start therapy with IR morphine followed by conversion to SR opioid therapy could be implemented as a standard therapy to manage moderate to severe chronic pain in patients with cancer or non-cancer pain. ORamorph® in TIBER study (ORTIBER).

Beyond the traditional definition of breakthrough pain: An observational study

IntroductionBreakthrough pain (BTP) is traditionally defined as a transitory pain flare in opioid-treated patients with chronic background pain. This definition has, however, been challenged in recent years. This study aimed to analyze BTP prevalence in different pain conditions.MethodsThis was a prospective, noninterventional, observational study conducted from June to September 2011 in two Italian pain treatment reference centres. Consecutive patients aged >18 years with oncological or non-oncological pain were eligible for this study; background pain was acute/ subacute (<3 months) or chronic (>3 months). The characteristics of pain were evaluated by means of a structured interview by physicians, and patients were asked to complete a dedicated clinical study form.The following outcomes were assessed: chronic pain duration (in patients with chronic pain), BTP prevalence, and number and severity of daily BTP episodes. All outcomes were assessed in four populations of patients with: (a) chronic oncological pain; (b) chronic non-oncological pain; (c) non-chronic oncological pain; (d) nonchronic non-oncological pain. The correlation between BTP and gender was also investigated.ResultsOf 1,270 patients with chronic pain, 1,086 had non-oncological pain (85.5%). Most patients (68.6%) with non-oncological pain were female (P = 0.001). Pain duration was significantly longer in non-oncological pain versus oncological pain groups (P = 0.002). BTP prevalence was lower in non-oncological patients (P < 0.001). No differences were reported in terms of number and severity of daily BTP episodes. BTP was more frequent in females with non-oncological pain (P = 0.04). Females had a significantly higher pain severity (P = 0.02) than males.ConclusionBTP is frequently reported in patients who do not have BTP according to the traditional definition. BTP frequency and severity is similar in oncological and non-oncological pain.

Adherence and long-term effect of oxycodone/paracetamol in chronic noncancer pain: a retrospective study

IntroductionLong-term administration of opiates in patients with chronic noncancer pain (CNCP) is subject to debate due to insufficient clinical evidence to support efficacy and tolerability.MethodsThis retrospective analysis used hospital records to investigate the effects of low doses of the combination of oxycodone/paracetamol on CNCP in an outpatient clinic setting to verify adherence to therapy and long-term efficacy. All patients receiving therapy for CNCP were examined between May and September 2010 and information was collected on medication, duration of therapy, and static and dynamic pain measured using numeric rating scales (NRS) from relevant charts.ResultsTwo hundred and thirty-one patients (157 men, 68%) with a mean (± SD) age of 66.4±15.5 years were analyzed. Pain indexes at baseline revealed a mean (± SD) static NRS (sNRS) of 3.5±1.77 and a mean dynamic NRS (dNRS) of 7.24±1.33. At last follow-up, mean (± SD) pain reductions versus baseline were 1.58±1.42 for sNRS and 3.04±1.43 for dNRS (P<0.0001 for both). Regarding the duration of therapy, 54 patients (23.4%) were treated for <4 months, and 177 patients (76.6%) for 4 months up to 23 months. Pain reduction was significant in all groups (P<0.0001) but was greatest in patients who had been receiving therapy for ≥4 months. Improvements in pain relief were not associated with an increase in daily dose, which remained stable or decreased slightly over time.DiscussionThe results of this study support the hypothesis that an opiate-based combination at low doses improves tolerability and adherence and results in patients obtaining long-term efficacy. Larger studies of the use of opiates in this setting and clinical monitoring on the regional and national level may convince clinicians to view opiates as efficacious analgesics and not as dangerous substances of abuse.

Effects of Opioid Rotation in Chronic Pain Patients: ORTIBARN Study

AbstractBackground: Opioid rotation is currently the subject of considerable debate for two reasons: firstly as a strategy for pain treatment, and secondly because of the difficulty in determining equianalgesic doses. Switching from one slow-release (SR) opioid analgesic to another raises a number of critical issues, and there are no widespread studies that support a standard protocol. Initiation of opioid therapy must consider gradual dose titration of the drug until the minimum effective and maximum tolerated dosage for each patient is found. Objective: This study aimed to evaluate the effects of SR opioid rotation after a stabilization period with normal-release (NR) morphine (‘start therapy’) in patients with cancer or non-cancer pain not controlled with their current SR opioid. Methods: This is a multicentre, open-label, prospective study. A total of 326 consecutive patients were enrolled who were affected by chronic cancer or non-cancer pain that was not controlled by an SR opioid administered as either monotherapy or in combination with other analgesic drugs. Following start therapy with oral NR morphine at a dosage of 5 mg or 10 mg every 4 hours, rotation to an SR opioid of a different type from that previously administered was carried out. Results: After about 3 days of start therapy with NR morphine, rotation to an SR opioid allowed a significant decrease of both baseline pain and daily episodes of breakthrough pain. No significant difference was detected between dosages and type of opioid administered, both prior to and after the start therapy period with NR morphine. Conclusions: Rotation to another opioid preceded by a brief period of opioid receptor resetting by start therapy with NR morphine allows a good level of pain control and avoids rotation to inappropriate opioid dosages or combinations analgesics.

Transdermal Buprenorphine in Non-Oncological Moderate-to-Severe Chronic Pain

AbstractBackground: Musculoskeletal pathologies are among the most frequent causes of long-term non-oncological severe pain and consequent physical impairment. Aims of pharmacological and physical therapy are to reduce pain, promote functional recovery and improve overall quality of life. Pharmacological therapy may include the use of opioids. Objective: To evaluate the efficacy and tolerability of transdermal buprenorphine (TDS) in the long-term management of non-oncological, chronic, moderate-to-severe musculoskeletal pain. Study Design: An open-label, prospective, single-centre, 6-month study. Setting: A ‘real world’ outpatient setting. Patients: Adult patients with chronic moderate-to-severe musculoskeletal pain were enrolled consecutively. Intervention: Patients initially received buprenorphine TDS 11.7 µg/h (onethird of 35 µg/h patch) every 72 hours. If required, patients could be uptitrated to 17.5 µg/h (one-half of 35µg/h patch), 23.4 µg/h (two-thirds of 35 µg/h patch) or 35 µg/h. Concomitant antiemetics were allowed. Main Outcome Measures: The primary endpoint was percentage mean reduction in static and dynamic pain visual analogue scale (VAS) scores at study end (10 being worst pain, 0 being no pain). Quality of life and tolerability were also assessed. Results: We enrolled 146 patients aged 41–94 years; their baseline mean± SD static and dynamic pain VAS scores were 6.87±1.89 and 7.70 ± 1.74, respectively. Buprenorphine TDS initial dosages were 11.7 µg/h (n=139), 17.5 µg/h (n = 4), 23.4 µg/h (n= 1) and 35 µg/h (n = 2). At 6 months, 89 patients were under treatment; 11% (n=10) were receiving 11.7µg/h, 30% (n = 27) 17.5 µg/h, 6% (n = 5) 23.4 µg/h and 53% (n = 47) 35µg/h. Patients achieved a nonsignificant reduction in pain at rest and in movement; mean ± SD static and dynamic pain VAS scores decreased to 1.56 ± 2.05 and 3.54 ± 2.02, respectively. The quality of life improved as shown by significant (p< 0.01) increases from baseline in all items relating to physical and mental health on the Short-Form 36 health survey. Patients experienced recovery of daily and social activities according to the significant (p<0.01) increase in Karnofsky Performance Status sub-item scores. Twenty-three patients discontinued treatment because of adverse events, which were mainly gastrointestinal or CNS-related. Conclusions: Low-dose buprenorphine TDS had good analgesic efficacy, and quality of life improved as early as 1 month after treatment initiation. Our results suggest that buprenorphine TDS is a well tolerated long-term analgesic for patients experiencing chronic musculoskeletal pain of moderateto-severe intensity.

Time to pain relief after immediate-release morphine in episodic pain: the TIME study.

AbstractBackground: Cancer-related and non-cancer chronic pain embodies the most frequent challenge in clinical practice. Management of chronic pain and breakthrough pain (BTP) requires adjustments to the analgesic regimen to achieve adequate pain control. Objective: To examine the time to achieve pain relief in patients who experienced intense episodic pain breakouts despite baseline therapy with analgesics. Methods: This study was based on a 14-day observation period. Patients with either cancer-related or non-cancer pain who experienced >2 intensive episodic pain breakouts per day were prescribed immediate-release (IR) morphine sulphate (10 mg to 20 mg as needed) every 4 hours (around-the-clock) and allowed one rescue dose of IR morphine (equal to one additional administration of the dosage taken at fixed times) for any episodic pain breakouts. Patients recorded time of administration and time taken to achieve partial or total relief of episodic pain breakout in daily diaries; in one study centre the diary was managed with the help of specialized medical attendants. Pain intensity and general wellbeing were assessed by a Numerical Rating Scale (NRS) and Karnofsky Performance Scale, respectively. Adverse events and sleep patterns were also recorded. Results: Of 85 patients (mean age 62.67 ± 14.3 years) enrolled, 14 experienced pain from non-cancer degenerative diseases, and 71 had cancer-related pain. Following stabilization of background pain, the intensity of daily pain improved; NRS decreased from baseline to day 14 for cancer (from 5.63 to 1.98) and non-cancer (from 8.00 to 1.00) groups (both p < 0.0001). Patients’ general wellbeing increased concomitantly. Around-the-clock therapy resulted in an immediate decrease in the number of intense episodic pain breakouts per day, with 11.8% of patients achieving total pain relief within 24 hours. The mean number of intense episodic pain breakouts per day decreased steadily in the cancer group, reaching significance at day 14 (p < 0.001 vs baseline). Moreover, the time to achieve partial and total pain relief of intense episodic pain breakouts improved significantly. Adverse events and sleep patterns improved over the 14-day observation period. Conclusions: Stabilization of background cancer-related or non-cancer pain with around-the-clock IR morphine therapy resulted in fewer intense episodic pain breakouts, which were more quickly managed with rescue-dose IR morphine, suggesting that ‘end-dose’ pain should not be classified as BTP.