Edoardo Arcuri

Gabapentin for Neuropathic Cancer Pain: A Randomized Controlled Trial From the Gabapentin Cancer Pain Study Group

PURPOSE To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain. PATIENTS AND METHODS One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opioid analgesics. RESULTS Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P =.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P =.0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%). CONCLUSION Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids.

Hyperalgesia: An Emerging Iatrogenic Syndrome

Clinical reports suggest that opioids, intended to abolish pain, can unexpectedly produce hyperalgesia. This paradoxical effect may be mechanistically related to tolerance induced by increasing doses of opioids. Two case reports illustrate a syndrome characterized by increasing pain pursued by escalating opioid doses, which results in a worsening of the clinical picture. Several experimental data may help explain the course of this challenging clinical condition. In escalating opioid doses rapidly, a risk of opioid-induced hyperalgesia should be recognized, as higher doses of opioids may stimulate rather than inhibit the central nervous system by different mechanisms. Alternative procedures should be taken into consideration to break this cycle, should it occur. More data are needed to detect this condition, as currently no diagnostic information on specific markers, clinical or biochemical, exists.

Hyperalgesia and opioid switching

Opioids, intended to abolish pain, can unexpectedly produce hyperalgesia, particularly during rapid opioid escalation. Opioid switching could be a therapeutic option in a condition of opioid-induced tolerance or hyperalgesia, but conversion ratios between opioids are difficult to apply in this context and require strict surveillance and expertise. This situation is challenging, because the rapid escalation of opioid doses, possibly due to the development of opioid-induced tolerance, can cause hyperalgesia. To avoid this adverse effect, clinicians need to refine their assessment of pain treatment and consider opioid switching. The authors present a case report in which switching from fentanyl to methadone was effective in a patient who developed hyperalgesia as a consequence of a rapid opioid escalation. Regardless of the expected clinical improvement of opioid switching using lower doses of the second opioid, the final dose of the second opioid was exaggeratedly low, probably as a consequence of the disappearance of hyperalgesia induced by the first opioid. The results of this case and others like it may help practitioners develop a meaningful approach during opioid escalation, possibly anticipating the need for opioid switching or other alternative measures for patients with uncontrolled cancer pain.

Pharmacological Management of Cancer Pain in the Elderly

Existing studies indicate a high prevalence rate and poor management of cancer pain in the elderly. Pain is often considered an expected concomitant of aging, and older patients are considered more sensitive to opioids. Despite the well known pharmacokinetic changes in the elderly, the complex network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult.Notwithstanding such difficulties, appropriate analgesic treatment is able to control cancer pain in the elderly in most cases. Skills necessary to optimise pain control in older cancer patients include the ability to objectively assess functional age (not necessarily related to chronological age since the rate of decline is variable), understand the impact of coexisting conditions, carefully manage the numbers and types of drugs taken at the same time and adequately communicate with patients and relatives.The most common treatment of cancer pain consists of the use of regularly given oral analgesics. The elderly are at increased risk of developing toxicity from NSAIDs, and the overall safety of these drugs in frail elderly patients should be considered. When older patients have clear contraindications to NSAIDs, manifest signs of toxicity from these agents, or find that pain is no longer controlled with this class of drugs, opioids should be started. A variety of opioids are available, and they differ widely with respect to analgesic potency and adverse effects among the elderly.Although the aged population requires lower doses of opioids, only careful titration based on individual response can ensure the appropriate response to clinical demand. Elderly patients are potentially more likely to be affected by opioid toxicity because of the physiological changes associated with aging. Nevertheless, appropriate dosage and administration may limit these risks. Cancer patients with pain who do not respond to increasing doses of opioids because they develop adverse effects before achieving acceptable analgesia may be switched to alternative opioids. Despite the favourable effects reported with opioid switching, monitoring is crucial, particularly in the elderly or patients who are switched from high doses of opioids. Adjuvant analgesics, including antidepressants, antiepileptics, corticosteroids and bisphosphonates may help in the treatment of certain types of chronic pain.With an appropriate and careful approach, it should be possible to reduce or eliminate unrelieved cancer pain in most elderly patients and, consequently, to enhance their quality of life. Older patients with cancer should be continuously assessed for cancer pain, both before and after analgesic treatment.

The MERITO Study: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during ‘titration phase’ in patients with cancer pain

Adequate and rapid pain control is one of the main goals of cancer pain treatment. The objective of this study was to assess the effect and tolerability of oral normal-release morphine during the initial phase of treatment in patients with moderate-to-severe cancer pain. Consecutive patients naïve to strong opioids received normal-release morphine 5 or 10 mg every 4 h during the titration phase (first 5 days), depending on previous analgesic therapy. Pain intensity was assessed using an 11-point Numerical Rating Scale (0–10), and data were recorded in a patient-compiled diary. The primary endpoint was the proportion of time with pain control (a reduction of at least 50% with respect to the baseline pain score) during the titration phase. A total of 159 consecutive patients (102 men; mean age 65 years) with cancer-related pain were enrolled. Pain control was observed for 75% (95% CI 70–80) of the follow-up period in the intent-to-treat population. Overall, 50% and 75% of patients achieved pain control within 8 and 24 h after starting normal-release morphine therapy respectively. The mean pain score was 7.63 points at baseline, and decreased to 2.43 and 1.67 points (both P < 0.001) at days 3 and 5 respectively. The most commonly reported adverse events were somnolence (24% of patients), constipation (22%), vomiting (13%), nausea (10%) and confusion (7%). Normal-release morphine results in rapid and satisfactory pain control, and is well tolerated, during the strong-opioid titration phase in patients with moderate-to-severe cancer pain.

Opioid switching and burst ketamine to improve the opioid response in patients with movement-related pain due to bone metastases.

ObjectiveTo improve opioid repsonse in patients with movement-related pain by using opioid switching adding a burst of ketamine. MethodsTwo patients with incident bone pain who had adverse effects with increasing doses of opioids were switched to methadone and a burst of 100 mg/d of ketamine for 2 consecutive days was added. ResultsBasal pain and pain on movement significantly improved. ConclusionsThe development of breakthrough pain due to movement (incident pain), associated with bone metastases is so rapid that no medication as needed has such a short onset to parallel this temporal pattern of pain firing. Experimental studies have shown that bone metastases are characterized by a specific pattern of spinal hyperexcitation requiring higher doses of opioids. Optimization of basal opioid regimen may improve mobilization. However, adverse effects may more likely occur. The role of opioid switching and burst ketamine to further improve the opioid response has never been assessed in this context. Further studies in animals could confirm these preliminary data, with specific design to parallel this clinical context.

Cutaneous bacterial colonization, modalities of chemotherapeutic infusion, and catheter-related bloodstream infection in totally implanted venous access devices

Goals of workProspective clinical study to evaluate patients suffering from solid tumor using a totally implanted venous access device (TIVAD) to determine: (1) if there is a relationship between cutaneous contamination at port insertion site and catheter-related bloodstream infection (CRBI); (2) development modalities of CRBI; (3) if there is a relationship between chemotherapy administration modalities by push/bolus versus continuous infusion and CRBI.Patients and methodsWe studied 41 consecutive patients who needed a TIVAD positioned for chemotherapy administration by bolus/push or continuous infusion. In every patient, we performed blood cultures from blood samples from port catheters and cutaneous cultures from cutaneous tampons of the skin surrounding the implant area on the first (T0) and eight day (T1) postoperatively, after 1 month (T2), and after 3 months (T3) from insertion.Main resultsThe study was completed on 40 patients; in one case, the port was removed at T2 for septic complications. We obtained four positive blood cultures (two, 5%), two in the same patient, all caused by staphylococcus. Positive cutaneous tampons were 21 (13%) in 11 patients (27%); the four CRBI occurred in this group of patients with none in the remaining 30 patients (73%) for a total number of 120 tampons (p<0.01). In two cases, the same germ was isolated from both the skin and blood. None of the patients presented a local infection of the subcutaneous pocket. Positive cutaneous cultures decrease over time: T0–T2, 24–5%; T1–T3, 20–5% (p<0.04). There were no differences in CRBI incidence and positive cutaneous tampons between the two chemotherapy administration modalities.ConclusionsCutaneous microbial flora has a primary role in CRBI development within TIVADs; there is a relationship between cutaneous colonization and CRBI; colonization reaches its maximum during the first days after catheterization in which the use of the system is at high risk; colonization occurs both via extraluminal and endoluminal routes; there is no difference in CRBI incidence between bolus and continuous infusion administration.

Opioid-induced hyperalgesia after rapid titration with intravenous morphine: Switching and re-titration to intravenous methadone

BACKGROUND Rapid titration with intravenous morphine (IV-MO) provides fast and efficient pain relief in cancer patients with severe-excruciating pain. However, some patients, after an initially favourable response, can develop an hyperexcitated state unrelieved or worsened by further dose increments. METHODS Eighty-one patients admitted on emergency basis titrated with IV-MO were assessed. RESULTS 12 patients were unsuccessfully titrated with IV-MO. Switching to intravenous methadone (IV-ME) and titrating the doses proved to be successfully. CONCLUSIONS In escalating opioid doses rapidly a recognition of the development of hyperalgesia should be suspected. Increasing doses of opioids may stimulate rather than inhibiting the central nervous system, with complex mechanisms already recognized in experimental studies. Switching to IV-ME and titrating the doses could be taken into consideration to break this vicious circle before pain conditions worsen irreversibly.

When the Progression of Disease Lowers Opioid Requirement in Cancer Patients

ObjectiveTo describe 2 cases in which an abrupt progression of disease compromising pain pathways and inducing some relief of existing pain or limiting drug delivery to central nervous system. MethodsCase reports which a significant decrease of opioid requirement was reported, either systematically and spinally. ResultsThe progression of disease produced changes in pain input or limited the effects of opioids given spinally. DiscussionThe data presented suggest that physicians should be aware of the possibility that opioid doses have to be reduced, where presumably specific events related to the progression of disease can change the pain syndrome or reduce the delivery of opioids when using particular routes of administration. This problem needs to be recognized and treated appropriately when it occurs.

Sympathetic blocks and disease progression modifying pain mechanisms

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