Adjuvant ketamine analgesia for the management of cancer pain

OBJECTIVE: To review the clinical literature evaluating the utilization of intravenous ketamine for the management of cancer-related pain, to summarize the data that suggest ketamine is an appropriate adjuvant method of providing analgesia and to report a case of successful pain management using ketamine in a patient with recurrent testicular cancer at our institution. DATA SOURCES: Primary literature was identified through a MEDLINE search (1966-March 2002), and additional information was obtained through secondary and tertiary sources. DATA SYNTHESIS: The available data suggest that supplementation of morphine with ketamine improves analgesia in patients with cancer, and also provides insight to the controversy regarding the efficacy and adverse effects of various ketamine doses. At subanesthetic doses, ketamine may be beneficial at reducing opioid requirements and related adverse effects. CASE SUMMARY: A 34-year-old white man with recurrent testicular cancer was admitted with radiating neuropathic pain of the legs and lower back. The patient was suspected to also be experiencing opioid adverse effects; therefore, alternative analgesic options were warranted. Ketamine was successful in reducing patient-reported pain and was also well tolerated. CONCLUSIONS: Ketamine is an adjuvant analgesic for the treatment of cancer-related pain when other agents either fail or are intolerable. Accordingly, there are several factors that may prevent adequate pain control with opioid use; therefore, alternative analgesic options should be considered. Promise exists for ketamine as a contemporary analgesic in the appropriate patient.     

PCA et douleur du cancer

Patient-controlled analgesia (PCA) is indicated for patients experiencing moderate to severe nociceptive cancer pain unrelieved by strong oral or transdermal opioids. This is appropriate in two situations: 1) the impossibility of oral or transdermal administration, and 2) inadequate control of breakthrough pain. Intravenous morphine remains the most frequently used opioid in PCA devices. Background infusion provides effective management of baseline pain; its dosage is calculated according to the daily amount of opioid previously taken by the patient. The bolus dose (ranging between 1/24 and 1/10 of the daily amount) is used as the breakthrough dose to treat breakthrough pain. In the case of renal insufficiency, fentanyl or sufentanil can be used. If the patient experiences refractory pain or opioid tolerance, it is possible to associate morphine with low doses of ketamine. Lastly, in the most difficult cases, the spinal route (epidural or intrathecal) may be an effective alternative in terms of improving of the quality of life of end-of-life patients.     

Continuous intravenous infusion of ketamine and lidocaine as adjuvant analgesics in a 5-year-old patient with neuropathic cancer pain

For difficult to treat neuropathic pain from cancer, adjuvant analgesics are often used with opioids. We present the case of a 5-year-old girl who was diagnosed with meningitis caused by malignant T-cell lymphoma. She had severe neuropathic pain not relieved by increasing doses of a fentanyl infusion. Intravenous administration of ketamine and lidocaine in combination with fentanyl provided excellent analgesia without significant side effects. Ketamine and lidocaine can be safely infused together with concomitant opioids for the treatment of refractory neuropathic pain caused by cancer.     

Effectively starting and titrating intrathecal analgesic therapy in patients with refractory cancer pain

Patients continue to suffer from pain despite their analgesic regimen and frequently from symptoms related to these interventions. This article describes the role that intrathecal analgesia may play in improving comfort for individuals experiencing refractory pain and/or symptoms of opioid therapy. Patient selection, staff education, institution requirements, medications, and titration guidelines also will be reviewed. Patients with cancer clearly deserve to achieve comfort; therefore, intrathecal therapy, which is a safe intervention, must be considered when refractory pain or symptoms occur.     

Opioid dose titration for severe cancer pain: a systematic evidence-based review

Dosing strategies to achieve rapid analgesia in patients with severe or crescendo cancer pain are important. A systematic review of research trials for treatment of severe or crescendo cancer pain was conducted; nine studies were identified. Eight trials were prospective; two were randomized between different dosing strategies. Dosing frequency predicted onset to analgesia regardless of baseline opioid dose. None of the trials were associated with evidence of respiratory depression. The studies all suffered significant methodological problems limiting broad conclusions. Until better data exist, opioid dose titration for severe/crescendo pain will be guided by expert opinion and experience.     

The use of ketamine in severe cases of refractory pain syndromes in the palliative care setting: a case series

The benefits of ketamine in reducing pain are largely based on case reports and small clinical trials. We present a case series describing the application and efficacy of subanesthetic doses of ketamine in the treatment of complex pain syndromes poorly responsive to escalating doses of opioids. The discussion that follows suggests that subanesthetic intravenous ketamine can be used to successfully treat severe pain of different etiologies refractory to opioid dose escalation. Optimal dosing titration, duration of initial treatment, and the role of maintenance ketamine need to be further elucidated. Our case series adds to the extant literature supporting the role of subanesthetic ketamine for refractory pain problems.     

Challenges Associated With Spinal Opioid Therapy for Pain in Patients With Advanced Cancer: A Report of Three Cases

Intraspinal opioid therapy has been increasingly used for the management of cancer pain refractory to traditional treatment. However, this approach may present challenges in patients with advanced cancer. Three cases are presented that highlight the challenges associated with using neuraxial analgesia to manage cancer pain that was felt to be “refractory” to conventional treatment. Before an invasive procedure, such as placement of a permanent intrathecal opioid delivery system, a rigorous assessment and treatment of total pain (physical, psychological, spiritual, social, and practical) by an interdisciplinary team would be prudent.     

Neuraxial pain relief for intractable cancer pain

Most patients with cancer pain achieve good analgesia using traditional analgesics and adjuvant medications; however, an important minority of patients (2% to 5%) suffers from severe and refractory cancer pain. For these individuals, spinal analgesics (intrathecal or epidural) provide significant hope for pain relief over months or years of treatment to help improve quality of life. Spinal analgesics have been suggested as the fourth step in the World Health Organization guidelines in the management of cancer pain, and thus the pain physician should be familiar with principles of use. Most patients achieve pain relief using spinal analgesics, with a minimum of complications that are easily managed at home. A variety of opioids, local anesthetics, clonidine, ketamine, and other analgesics are available for the spinal route of administration and should be titrated to clinical effect or intolerable side effect. This article discusses the appropriate selection of patients for spinal analgesics, reviews current recommended infusion systems and current spinal analgesics, discusses possible complications, and includes practical suggestions for patient management.     

Ketamine as an adjuvant for treatment of cancer pain in children and adolescents.

In children with advanced stages of cancer, pain control remains inadequate in many patients and a solution to this problem is sorely lacking. Factors related to progression of the primary disease and side-effects of high doses of opioids, the mainstay of pain therapy, contribute to the inadequacy of pain control. In addition, few studies suggest that opioids, by inducing tolerance, having pronociceptive effects and producing hyperalgesia in some patients, can also contribute to inadequacy of pain control. Researchers have shown that N-methyl-D-aspartate (NMDA) receptor antagonists may have a role in mitigating opioid-induced tolerance and hyperalgesia in adults. However, literature on NMDA antagonists to treat cancer pain in children and adolescents is scarce. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and yet had uncontrolled cancer pain. A low-dose ketamine infusion was administered to all patients to modulate the need for rapidly escalating opioid therapy. We found that in 8 of 11 patients, ketamine infusions used as an adjuvant to opioid analgesia was associated with opioid-sparing effects and apparent improvement in pain control and in the children's ability to interact with their family. This study suggests that infusions of ketamine may offer a promising therapeutic option in the treatment of appropriately selected children and adolescents with intractable cancer pain. PERSPECTIVE: In many children with advanced stages of cancer, pain control remains inadequate. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and had uncontrolled cancer pain. In the majority of patients, ketamine appeared to improve pain control and to have an opioid-sparing effect.     

Ketamine for pain relief in acute pancreatitis

Patients with acute pancreatitis are often admitted to critical care unit and present with a spectrum of multiorgan problems. The commonest presenting symptom of acute pancreatitis is upper abdominal pain. The pain can be very severe and refractory to the treatment with conventional analgesics. The pain not only adds to the patient's distress but may also have adverse effects on the cardio-respiratory systems, which can be affected by acute pancreatitis itself. The pain in acute pancreatits is usually controlled by conventional analgesics, morphine/pethidine PCA or epidural analgesia. But at times all these measures of pain control fail and additional methods of pain relief become necessary. We encountered a patient with acute pancreatits with severe abdominal pain in whom conventional methods of pain relief failed to provide adequate analgesia. The patient had respiratory impairment secondary to upper abdominal pain and improved pain relief avoided the possible need for invasive ventilation. We used an intravenous ketamine infusion to supplement the analgesic regimen with a significant improvement in pain relief without any adverse psycho mimetic effects. The probable mechanisms of action of ketamine in improving pain relief are discussed. On search of the literature, the use of ketamine for pain relief in acute pancreatitis has never been reported.     

Transient amnesia following prehospital low-dose ketamine administration

Low doses of ketamine have been shown to be safe and effective for pain relief. Adverse effects are generally mild and transient. A 69-year-old woman suffered a witnessed ground-level fall without report of head injury, loss of consciousness, or intoxication. She was in severe pain despite 10 mg of intravenous morphine and paramedics provided intravenous ketamine 16 mg (0.19 mg/kg). Upon arrival to the ED, she was alert and oriented. An X-ray demonstrated an acute comminuted nondisplaced right humeral head and neck fracture. Her pain improved after an additional 4 mg of morphine and placement of a sling. Prior to discharge, the patient developed confusion, difficulty finding words, amnesia to the event, and anterograde amnesia evidenced by repetitive questioning. A head CT and a CT angiogram of the patient's head and neck demonstrated no acute abnormalities and an EEG demonstrated no epileptiform activity. The patient was admitted for observation and her mental status gradually improved overnight. She was discharged the following morning. Low dose ketamine is an important therapeutic option. Delayed or prolonged neuropsychiatric effects may be possible following combined ketamine and opioid analgesia. Clinicians utilizing low dose ketamine should be aware of this potential complication as it could result in the need for additional diagnostic testing and prolonged length of stay.     

Ketamine as adjuvant to opioids for cancer pain. A qualitative systematic review

Ketamine is increasingly being used as an adjuvant to opioids in the treatment of refractory cancer pain. This systematic review examines the available evidence. Randomized, controlled trials, with or without crossover, were included. Studies were identified from MEDLINE, EMBASE, CANCERLIT, the Cochrane Library, handsearched reference lists from review articles and chapters from standard textbooks on pain and palliative care and reference lists from papers retrieved. Four randomized, controlled studies were identified. Two were excluded due to poor quality. Both included studies concluded that ketamine improves morphine treatment in cancer pain. Quantitative meta-analysis was not possible. The available evidence is not sufficient to conclude that ketamine improves the effectiveness of opioid treatment in cancer pain. High quality, randomized, controlled trials with larger numbers of patients and standardized, clinically relevant routes of administration of ketamine are needed.     

The role of ketamine in pain management.

Ketamine is a dissociative anaesthetic; its mechanism of action is primarily an antagonism of the N-methyl-D-aspartate (NMDA) receptor. The role of ketamine, in particular in lower sub-anaesthetic doses, has recently gained increasing interest in pain management. It has been studied in a considerable number of trials and analysed in meta-analyses and systematic reviews. Based on these data, the primary role of ketamine in such low doses is as an 'anti-hyperalgesic', 'anti-allodynic' or 'tolerance-protective' agent. It therefore has a role in the treatment of opioid resistant or 'pathological' pain (central sensitisation with hyperalgesia or allodynia, opioid induced hyperalgesia, neuropathic pain) rather than as an 'analgesic' in its own right. Low dose ketamine also has 'preventive analgesia' properties. Furthermore, in higher doses it provides effective and safe sedation and analgesia for painful procedures. The place of ketamine in the treatment of chronic pain and the effects of long-term medicinal use remain unclear.     

Effects of preincisional ketamine treatment on natural killer cell activity and postoperative pain management after oral maxillofacial surgery

Poorly controlled pain may lead to increased risk of cancer metastasis by suppressing natural killer (NK) cell activity. Ketamine may be beneficial by potentiating opioid-induced analgesia. We enrolled 59 participants in a randomized double-blind, placebo-controlled clinical trial and assigned them to receive propofol plus (1) saline, 2 mL; (2) ketamine, 0.5 mg/kg; or (3) ketamine, 1.2 mg/kg, followed by a standardized anesthesia protocol. The visual analogue scale (VAS) and 24-hour opioid consumption measured postoperative pain perception. NK cell activity was measured before and 24 hours after ketamine administration using the chromium 51 release assay. Nonparametric analysis of VAS data revealed that women receiving 0.5 mg/kg of ketamine reported less pain (P <.05) compared with the saline 1.2 mg/kg-ketamine groups. This finding was not evident in men. Comparing opioid consumption among the 3 groups (using analysis of variance) revealed a drug-gender interaction (P < .05): 0.5 mg/kg of ketamine decreased postoperative opioid consumption for women more than for men. Although not statistically significant, women receiving 0.5 mg/kg of ketamine had the least NK cell suppression compared with preoperative values (repeated analysis of variance). These findings suggest that for women, low-dose ketamine may be beneficial.     

Methylene Blue for the Treatment of Intractable Pain Associated with Oral Mucositis

Oral mucositis is a common and often debilitating complication among cancer patients receiving radiation therapy to the head and neck or chemotherapy agents, or undergoing hematopoietic stem cell transplantation. Pain and decreased oral function associated with oral mucositis may persist long after the conclusion of therapy. Although most patients respond to conservative management, a subset of patients develops intractable pain with severe consequences. For some, the use of total parenteral nutrition with insertion of percutaneous endoscopic gastrostomy feeding tubes is the only alternative. Current recommendations to treat mucositis and its related pain include basic oral care, bland oral rinses, topical anesthetics, and systemic analgesics. We believe that chemical neurolysis of the affected areas with methylene blue used as an oral rinse is a noninvasive, efficient, safe, and cost‐effective alternative that can provide prolonged analgesia in patients with intractable pain of oral mucositis. The benefits of this therapy are reflected in its improvement of patients’ quality of life by enabling oral feeding and controlling pain. We report a series of 5 consecutive patients with intractable oral mucositis‐related pain despite conventional treatment with systemic opiates. All 5 patients responded well to the use of 0.05% methylene blue as mouth rinse, demonstrating sustained analgesia over 3 weeks. The treatment was tolerated well, and overall patient satisfaction was very high. We also observed that methylene blue rinse significantly reduced the total opioid requirement, as demonstrated by reductions in the patients’ morphine equivalent daily dose scores after its use. Our case series suggests that 0.5% methylene blue oral rinse therapy is an effective and inexpensive modality that can be used safely to palliate intractable oral pain in patients with mucositis associated with cancer treatment. To our knowledge, this is the first report using this therapy to treat pain from oral mucositis.     

小剂量氯胺酮辅助吗啡硬膜外/皮下自控镇痛用于顽固性中、重度晚期癌痛治疗的临床研究

目的:观察小剂量氯胺酮辅助吗啡硬膜外或皮下自控镇痛(PCEA/PCSA)用于顽固性中、重度晚期癌痛患者的可行性及止痛效果.方法:选择54例中、重度晚期癌痛患者,均为虽经三阶梯药物治疗方案治疗未能很好地控制疼痛,同时毒副作用较大的患者.按是否可以行硬膜外穿刺置管分成两组,硬膜外自控镇痛(PCEA)组(n=28例)和皮下自控镇痛(PCSA)组(n=26例).采用硬膜外自控镇痛组,镇痛液为200ml,内含吗啡20mg+氯胺酮100mg.皮下自控镇痛组200ral内含吗啡80mg+氯胺酮400mg.分别在安装止痛泵后24小时、48小时采用视觉模拟评分法(VAS)评估疼痛程度,统计两组不良反应的发生率.结果:经治疗,两组病例疼痛明显缓解.两组间视觉模拟评分(VAS)各时段无统计学差异(P>0.05).吗啡和氯胺酮用量PCSA组明显多于PCEA组,PCEA组生活总满意度明显高于PCSA组.不良反应:恶心呕吐、便秘、嗜睡、皮肤瘙痒、尿潴留Pc.SA组明显高于PCEA组;呼吸抑制、幻觉发生率两组无差异.结论:本研究结果表明,小剂量氯胺酮辅助吗啡硬膜外或皮下自控镇痛都可以有效治疗中/重度晚期顽固性癌痛.经硬膜外小剂量氯胺酮辅助吗啡自控镇痛具有镇痛作用强、用药量少、副作用小等优点,皮下自控镇痛可作为硬膜外自控镇痛的有效补充.     

Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy

Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy.     

Opioidanalgetika bei “nichtmalignen” Schmerzen—Langzeitbehandlungsergebnisse bei Patienten mit rheumatischen Beschwerden

The oral administration of strong opioids like morphine is a very effective treatment in cancer pain. However, these analgesics are rarely prescribed for patients suffering from severe "non-malignant" pain. We examined the effects of oral opioids (morphine sulphate tablets, buprenorphine and levomethadone) given to patients with intractable rheumatic pain, which were refractory to other therapeutic measures. The origin of pain was inflammation or a degenerative lesion of the spine. Within a period of more than 3 years, 12 patients were treated accordingly. In 9 patients we could achieve sufficient pain relief, two of them showing improvement only after having changed the initially prescribed drug. We had to stop opioid medication in two patients because of side-effects and, moreover, in one patient because of failure to produce analgesia. 775 weeks of treatment were documented until December 31th, 1990, with an individual duration ranging from 11 to 145 weeks. It was necessary to increase the dose of morphine in the course of treatment of one patient, who is up to now being treated for more than 77 weeks. In all other patients the doses were either stable or varied. No severe side-effects such as respiratory depression were associated with long-term opioid therapy. Constipation was observed in 4 patients, nausea in two patients and urinary retention in one patient. These side-effects could be well treated by an additional medication. No drug abuse, dependence or tolerance were observed. Strong opioids are not analgesics of first choice in patients with rheumatic disease, but an opioid medication should be considered-as well as in patients with intractable pain caused by another disease-when alternative therapeutic measures have failed. The principles of opioid medication in rheumatic pain are similar to those in patients with cancer pain.