Opioid-induced hyperalgesia

Recently it became clear that opioids, besides their role in analgesia, mayalso induce hyperalgesia. Something what in the past was called opioidneurotoxicity. Hyperalgesia, or hypersensitivity to pain stimuli may berelated to well known problems of tolerance to opioids. Hyperalgesia is amajor clinical problem and its recognition and treatment are of paramountimportance. It is believed that uncoupling of opioid receptors from theGi/Go proteins and coupling them to Gs protein changes dramatically activityof opioid receptors. In this article the different aspects of diagnosis andtreatment of hyperalgesia are discussed.Recently it became clear that opioids, besides their role in analgesia, mayalso induce hyperalgesia. Something what in the past was called opioidneurotoxicity. Hyperalgesia, or hypersensitivity to pain stimuli may berelated to well known problems of tolerance to opioids. Hyperalgesia is amajor clinical problem and its recognition and treatment are of paramountimportance. It is believed that uncoupling of opioid receptors from theGi/Go proteins and coupling them to Gs protein changes dramatically activityof opioid receptors. In this article the different aspects of diagnosis andtreatment of hyperalgesia are discussed

Is there enough evidence to advocate opioid combinations? Does one and one make two or more?

Despite a more than tenfold increase in opioid consumption in the past decades, many cancer patients still suffer pain. The current understanding of this situation is poorly understood. It is still possible that in some countries pain is still undertreated, but it is also possible that we do not appreciate opioid induced toxicity and other phenomena an/or our opioid prescribing needs to be refreshed. At the moment the only evidence based tool to deal with opioid toxicity is switching to another opioid. Other methods are also described, but are far less well evidenced. However, the effects after switching are short-lived and sometimes a number of switches are needed. In this article we discuss the rationale behind and the possibility of combining different opioids with each other. Opioids are all different and opioid receptors are heterogenous. There are data to suggest that widening the activity spectrum of opioids may be the way forward in order to decrease adverse effects and maintain analgesia. At the moment there are only some data on the interaction of fentanyl and morphine, morphine and oxycodone, and buprenorphine and morphine. These data suggest that we should investigate these problems vigorously and, instead of switching from one opioid to another, we may, in future, adopt the concept of a semi-switch, where the dose of the first opioid is decreased and a second opioid is added. Adv. Pall. Med. 2010; 9, 2: 31–38Despite a more than tenfold increase in opioid consumption in the past decades, many cancer patients still suffer pain. The current understanding of this situation is poorly understood. It is still possible that in some countries pain is still undertreated, but it is also possible that we do not appreciate opioid induced toxicity and other phenomena an/or our opioid prescribing needs to be refreshed. At the moment the only evidence based tool to deal with opioid toxicity is switching to another opioid. Other methods are also described, but are far less well evidenced. However, the effects after switching are short-lived and sometimes a number of switches are needed. In this article we discuss the rationale behind and the possibility of combining different opioids with each other. Opioids are all different and opioid receptors are heterogenous. There are data to suggest that widening the activity spectrum of opioids may be the way forward in order to decrease adverse effects and maintain analgesia. At the moment there are only some data on the interaction of fentanyl and morphine, morphine and oxycodone, and buprenorphine and morphine. These data suggest that we should investigate these problems vigorously and, instead of switching from one opioid to another, we may, in future, adopt the concept of a semi-switch, where the dose of the first opioid is decreased and a second opioid is added. Adv. Pall. Med. 2010; 9, 2: 31–3

Intranasal fentanyl versus fentanyl pectin nasal spray for the management of breakthrough cancer pain in doses proportional to basal opioid regimen.

Abstract The aim of this randomized, crossover, comparison study was to assess the analgesic and adverse effects of 2 nasal preparations, intranasal fentanyl (INFS) and fentanyl pectin nasal spray (FPNS), for breakthrough pain, given in doses proportional to opioid basal regimen. Each patient randomly received INFS or FPNS in doses proportional to opioid dosages used for background analgesia for 2 pairs of episodes. For each episode of breakthrough pain, pain intensity and adverse effects intensity were recorded just before starting the INFS or FPNS (T0) and 5 minutes (T5), 10 minutes (T10), and 20 minutes (T20) after the administration of the nasal drugs. Sixty-nine patients were studied. The mean age was 63.4 years, and 37 patients were males. For the present analysis, 188 episodes were considered. A statistical decrease in pain intensity was observed with both nasal drugs after 5, 10, and 20 minutes. A decrease in pain intensity of >33% was observed in 16, 102, and 159 treated episodes at T5, T10, and T20, respectively. Adverse effects were of mild nature in most cases or were preexistent because of basal opioid therapy. No differences were found in summed pain intensity difference 20 minutes after dosing. Most of patients did not find substantial preferences. INFS and FPNS were effective and well-tolerated treatments for breakthrough pain management. Both delivery systems, in doses proportional to the basal opioid regimen, provided significant analgesia within 10 minutes, without producing relevant adverse effects. PERSPECTIVE: This article showed that INFS and FPNS in doses proportional to basal opioid regimen are equally safe and effective for the management of breakthrough pain in cancer patients. These data provide new insights on the use of nasal preparations of fentanyl

Czy jest wystarczająco dużo dowodów, aby zalecać kojarzone stosowanie opioidów? Czy jeden plus jeden tworzy dwa czy może więcej?

Mimo ponad 10-krotnego wzrostu zużycia opioidów w ostatnich dekadach, nadal wielu pacjentów z chorobą nowotworową cierpi z powodu bólu. Obecny stan wiedzy w tej dziedzinie jest jeszcze niezadowalający. Z jednej strony, ból jest wciąż niedostatecznie leczony, jak to ma miejsce w niektórych krajach, a z drugiej, "zapomina się" o toksyczności opioidów, stosując zbyt wysokie dawki. W związku z tym należy zaktualizować wiedzę dotyczącą leków opioidowych. Obecnie jedyną udowodnioną metodą zmniejszenia toksyczności opioidów jest ich rotacja (inne metody są znacznie mniej zbadane). Niestety, pozytywne skutki zamiany jednego środka na drugi są krótkotrwałe i czasem rotacji leków należy dokonywać kilkukrotnie. W niniejszym artykule omówiono zasadność oraz możliwość stosowania kombinacji różnych opioidów. Leki te różnią się od siebie, a ich receptory wykazują heterogenność. Wiele danych wskazuje na to, że poszerzenie spektrum działania opioidów poprzez ich skojarzenie może prowadzić do zmniejszenia ryzyka działań niepożądanych, przy utrzymaniu efektu przeciwbólowego. Obecnie są znane tylko badania dotyczące łączenia fentanylu z morfiną, morfiny z oksykodonem oraz buprenorfiny z morfiną. Z uzyskanych danych wynika, że w przyszłości leczenie powinno się opierać na koncepcji niepełnej rotacji, której celem jest obniżenie dawki pierwszego opioidu i dodanie drugiego, a całkowitą zamianę jednego leku na drugi należy zastąpić tą nową metodą. Medycyna Paliatywna w Praktyce 2010; 4, 3: 111-11

Methadone as First-line Opioid for the Management of Cancer Pain

Aim The aim of this study was to assess the efficacy and adverse effects of methadone when used as first-line therapy in patients that are either receiving low doses of opioids or none. Methods Patients with advanced cancer were prospectively assessed. Opioid-naive patients (L-group) were started with methadone at 6 mg/day. Patients receiving weak or other opioids in doses of <60 mg/day of OME (H-group) were started with methadone at 9 mg/day. Methadone doses were changed according to the clinical needs to obtain the most favorable balance between analgesia and adverse effects. Edmonton Symptom Asssement Score (ESAS), Memorial Delirium Assessment Score (MDAS), doses of methadone, and the use of adjuvant drugs were recorded before starting the study treatment (T0), 1 week after (T7), 2 weeks after (T14), 1 month after (T30), and 2 months after (T60). Methadone escalation index percent (MEI%) and in mg (MEImg) were calculated at T30 and T60. Results Eighty-two patients were assessed. In both groups H and L, there were significant changes in pain and symptom intensity at the different times during the study. Adverse effects as causes of drop-out were minimal. Mean MEImg was 0.09 (SD 0.28) and 0.02 (SD 0.07) at T30 and T60, respectively. MEI% was 1.01 (SD 3.08) and 0.27 (SD 0.86) at T30 and T60, respectively. Conclusion Methadone used as a first-line opioid therapy provided good analgesia with limited adverse effects and a minimal opioid-induced tolerance

From "Breakthrough" to "Episodic" Cancer Pain? A European Association for Palliative Care Research Network Expert Delphi Survey Towards a Common Terminology and Classification of Transient Cancer Pain Exacerbations

Context: Cancer pain can appear with spikes of higher intensity. Breakthrough cancer pain (BTCP) is the most common term for the transient exacerbations of pain, but the ability of the nomenclature to capture relevant pain variations and give treatment guidance is questionable. Objectives: To reach consensus on definitions, terminology, and sub classification of transient cancer pain exacerbations. Methods: The most frequent authors on BTCP literature were identified using the same search strategy as in a systematic review and invited to participate in a two-round Delphi survey. Topics with a low degree of consensus on BTCP classification were refined into twenty statements. The participants rated their degree of agreement with the statements on a numeric rating scale (NRS 0-10). Consensus was defined as a median NRS score of ≥ 7 and an interquartile range of ≤ 3. Results: Fifty-two authors had published three or more papers on BTCP over the past ten years. Twenty-seven responded in the first round and 24 in the second round. Consensus was reached for 13 of 20 statements. Transient cancer pain exacerbations can occur without background pain, when background pain is uncontrolled, and regardless of opioid treatment. There exist cancer pain exacerbations other than BTCP, and the phenomenon could be named “episodic pain”. Patient reported treatment satisfaction is important with respect to assessment. Sub classification according to pain pathophysiology can provide treatment guidance. Conclusion: Significant transient cancer pain exacerbations include more than just BTCP. Patient input and pain classification are important factors for tailoring treatment

The effects of low doses of pregabalin on morphine analgesia in advanced cancer patients

Abstract OBJECTIVES: The aim of this study was to evaluate the opioid response in patients receiving morphine and pregabalin, independently from the presumed pain mechanisms, in comparison with patients receiving morphine treatment only. METHODS: A multicenter prospective randomized controlled study was carried out in a sample of 70 advanced cancer patients with pain requiring strong opioids. Thirty-five patients (group MO) were randomized to receive sustained-release morphine using initial doses of 60 mg/day. Thirty-five patients (group MO-PR) were randomized to start the same morphine doses and pregabalin in increasing doses, starting with 25 mg/day up to 150 mg/day in one week. The following data were also recorded before starting the treatments (T0) and then at week intervals for four weeks (W1-4): age, gender, primary cancer and known metastases, pain causes and mechanisms, symptoms associated with opioid therapy, pain intensity, Brief Pain Inventory (BPI), morphine doses and escalation indexes (OEIs), and quality of life. RESULTS: Forty-eight patients completed the study, twenty-eight and sixteen patients in group MO and MO-PR, respectively. Twenty patients were females, the mean age was 65.5 (± 10.3), and the mean Karnofsky status was 66.0 (± 18.9). No differences between groups were found in age (P = 0.839), Karnofsky status (P = 0.741), opioid doses as well as escalation indexes (OEI mg, P = 0.260, and OEI%, P = 0.270). No differences between the two groups were found in quality of life and all BPI items. CONCLUSION: The use of low doses of pregabalin added to morphine therapy in advanced cancer patients does not seem to provide advantageous analgesic effects, despite limitations of the present study due to the number of drop-outs

Oxycodone/Acetaminophen: The Tailoring Combination Treatment for Specific Clinical Profile of Opioid Well-Responsive Cancer Pain

Background: International guidelines recommend moderate-to-severe cancer pain to be treated with strong opioids. However, pain management remains an unsolved matter, at least in the demanding oncology and palliative care setting. Although cancer pain consists of multiple components, which interact in complex ways where combination therapy can better intercept multiple pain characteristics, few studies have used a non-opioid/opioid association to exploit possible synergistic actions. Even the efforts of a recent approach emphasizing appropriate pain assessment and accurate classification to obtain personalized pain management have not produced a satisfactory analgesic strategy. Objective: This analysis was intended to evaluate the effectiveness of the immediate release fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of moderate-to-severe intensity background pain used alone or in combination with other strong opioids in cancer patients with breakthrough cancer pain (BTcP). This is a secondary analysis of a wider observational, prospective, multicenter study [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] performed on 179 patients treated with opioids for cancer pain who received the fixed combination of oxycodone/acetaminophen (OxyIR/Par) for the treatment of background pain (BGP). Results: Cancer patients with breakthrough cancer pain and controlled BGP (Background Pain) were classified according to the presence of analgesic therapy with tablets of fixed combination OxyIR/Par alone (group A, n=120) or tablets of fixed combination OxyIR/Par combined with other strong opioids (group B, n=59). Clinical features of group A were different to group B: higher mean Karnofsky Performance Status Index 70.3% (95% CI=67.2-73.5; median=70, CI=60-80) vs 58.3 (95% CI=53.4-63.2; median=50, CI=45-70) (P<0.001), and mainly group A patients were treated in an ambulatory setting (55.0% group A vs 33.9% group B) (p<0.001). Both groups had managed BGP with similar mean dosages (group A: 12.0, CI=10.5-13.4; group B: 13.1, CI=11.0-15.1) and frequencies of OxyIR/Par alone for group A and in association to other opioids for group B, but Breakthrough cancer Pain (BTcP) exhibited different characteristics in the two groups, showing a lower mean intensity numerical rating scale (NRS) of 7.5 (95% CI=7.2-7.7; median=7, CI=7-8 group A) vs 7.9 (95% CI=7.6, 8.2; median= 8, CI=7-9 group B) (P=0.04) and a higher percentage of patients had a faster onset, defined as the maximum intensity reached in less than 10 minutes, 81.7% (N=98) in group A vs 59.3% (n=35) in group B (P=0.002). Conclusion: This is the first analysis about the efficacy of an immediate-release fixed combination of OxyIR/Par in the real world for moderate-to-severe background cancer pain and breakthrough cancer pain. The oral fixed combination OxyIR/Par provided an adequate level of analgesia for moderate-severe background cancer pain, in a different cohort of cancer patients with different performance status, both in ambulatory and palliative settings. The low dosage of fixed combination OxyIR/Par was effective alone or in association with other opioids

Careful breakthrough cancer pain treatment through rapid-onset transmucosal fentanyl improves the quality of life in cancer patients: results from the best multicenter study

Objectives: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain. Methods: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain (numeric rating scale, NRS <= 4) during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS). RESULTS: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear p-value = 0.1) and dyspnea (Linear p-value = 0.05). The ESAS and PSQI questionnaires confirmed these positive results (p < 0.0001 and p = 0.002, respectively). Conclusions: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance