Qutaiba Amir Tawfic

A review of the use of ketamine in pain management

Ketamine is a noncompetitive antagonist of N-methyl-d-aspartate receptor. It has been widely used in anesthesia and pain management. Ketamine has been administered via the intravenous, intramuscular, subcutaneous, oral, rectal, topical, intranasal, sublingual, epidural, and caudal routes. Ketamine improves postoperative and posttrauma pain scores and reduces opioid consumption. It has special indication for patients with opioid tolerance, acute hyperalgesia, and neuropathic pain. It also has a role in the management of chronic pain including both cancer and noncancer pain. Recreational use of ketamine is increasing as well through different routes of administration like inhalation, smoking, or intravenous injection. Long-time exposure to ketamine, especially in the abusers, may lead to serious side effects. This review is trying to define the role of ketamine in pain management.

The Role of a Low-Dose Ketamine-Midazolam Regimen in the Management of Severe Painful Crisis in Patients With Sickle Cell Disease

CONTEXT Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. OBJECTIVES We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. METHODS A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. RESULTS Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). CONCLUSION Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect.

Postoperative pain management in patients with chronic kidney disease

Chronic kidney disease (CKD) is a health care problem with increasing prevalence worldwide. Pain management represents one of the challenges in providing perioperative care for this group of patients. Physicians from different specialties may be involved in pain management of CKD patients, especially in advanced stages. It is important to understand the clinical staging of kidney function in CKD patients as the pharmacotherapeutic pain management strategies change as kidney function becomes progressively impaired. Special emphasis should be placed on dose adjustment of certain analgesics as well as prevention of further deterioration of renal function that could be induced by certain classes of analgesics. Chronic pain is a common finding in CKD patients which may be caused by the primary disease that led to kidney damage or can be a direct result of CKD and hemodialysis. The presence of chronic pain in some of the CKD patients makes postoperative pain management in these patients more challenging. This review focuses on the plans and challenges of postoperative pain management for patient at different stages of CKD undergoing surgical intervention to provide optimum pain control for this patient population. Further clinical studies are required to address the optimal medication regimen for postoperative pain management in the different stages of CKD.

Acute pain service: past, present and future

Post surgical pain is a continuing major medical challenge despite all the advances in understanding acute pain and the development of new modalities of pain management. Since 1985 when the first acute pain service (APS) was started, many organizations initiated APS protocols and guidelines and it became mandatory to have an APS in all major acute care centers. This review focuses on the stages of development of APS and the challenges of postoperative pain management to provide optimal analgesia. Further clinical studies are required to determine best medication regimen for post-operative pain management.

Ultra-low-dose ketamine infusion for ischemic limb pain

To the Editor, Ketamine is widely used in acute pain management and has found special application in patients with opioid tolerance, acute hyperalgesia, and chronic neuropathic pain. We report the pain management of a patient with ischemic limb pain using an ultra-low-dose ketamine infusion. A 40-yr-old male (80 kg, American Society of Anesthesiologists’ physical status IV) with a complex medical history (diabetes mellitus type 2, diabetic neuropathy, end-stage renal disease on peritoneal dialysis, peripheral vascular disease, and hypertension) presented with worsening ischemia of his right leg. Initially, he underwent below-knee amputation under epidural anesthesia, and the epidural was continued for analgesia for three days after surgery. After the epidural was discontinued, oral multimodal analgesia with acetaminophen (650 mg po q4h), pregabalin (50 mg po q am), tramadol (25 mg po q12h), and nortriptyline (10 mg po qhs). In addition, he was prescribed intermittent doses of hydromorphone (0.5 mg sc or 1-2 mg po q4h prn) for breakthrough pain. The patient appeared to be very sensitive to these small doses of opioids he complained of nausea, vomiting, sedation, and hallucinations. These side effects limited the amount of opioid that could be used, and his pain continued to be inadequately controlled. He remained in hospital for another three weeks with worsening pain due to poor healing of the stump. The patient’s pain became difficult to control and he refused any opioid analgesia. At this point, the surgeons reconsulted the Acute Pain Service (APS). On evaluation, the patient reported a pain score (numerical rating score 0-10) of 8/10 at rest and 12/10 with movement. In addition to phantom pain and allodynia, he described pain in the amputated leg as shooting, sharp, and thunder-like. After careful discussion, the APS physician administered a small ‘‘test’’ dose of ketamine (2 mg iv q 15 min, 6 mg total). The pain decreased dramatically to 4/10 without any psychomimetic side effects. A decision was made to stop the intermittent opioids and to start a ketamine infusion at 1.5-5 mg hr. Three days after initiating the ketamine infusion, the surgeons decided to proceed with above-knee amputation due to persistent stump ischemia and infection. Surgery was done under general anesthesia supplemented with a single-shot femoral nerve block. Postoperatively, opioids were not prescribed and the ketamine infusion was re-initiated. The ketamine infusion was titrated to provide analgesia (within the range of 1-5 mg hr) and continued for four days. Daily ketamine requirement and pain scores are shown in the Figure. The patient was discharged home after one week with minimal pain and no side effects from the ketamine. He continued to take pregabalin (25 mg bid) and tramadol (25 mg prn) with consistent pain scores of 3/10 at rest and 5/10 with activity. He remained well at follow-up six months after his amputation and returned to the operating room for an uneventful revascularization of his other leg. The effective treatment of ischemic limb pain remains a clinical and pharmacological challenge. There is evidence suggesting that neuropathic mechanisms play a major role in this type of pain due to ischemia or direct damage to the nerve. One other explanation for neuropathic pain may be the N-methyl-D-aspartate receptor-mediated increases in synaptic excitability of the spinal cord, clinically manifested as hyperalgesia and allodynia. Ischemic limb Q. A. Tawfic, MBChB N. Eipe, MD (&) J. Penning, MD Department of Anesthesiology, The Ottawa Hospital, Ottawa, ON, Canada e-mail: neipe@toh.on.ca

Adult Sickle Cell Disease : A Five-year Experience of Intensive Care Management in a University Hospital in Oman

OBJECTIVES Sickle cell disease (SCD) is an inherited disease caused by an abnormal type of haemoglobin. It is one of the most common genetic blood disorders in the Gulf area, including Oman. It may be associated with complications requiring intensive care unit (ICU) admission. This study investigated the causes of ICU admission for SCD patients. METHODS This was a retrospective analysis of all adult patients ≥12 years old with SCD admitted to Sultan Qaboos University Hospital (SQUH) ICU between 1st January 2005 and 31st December 2009. RESULTS A total number of 49 sickle cell patients were admitted 56 times to ICU. The reasons for admission were acute chest syndrome (69.6%), painful crises (16.1%), multi-organ failure (7.1%) and others (7.2%). The mortality for SCD patients in our ICU was 16.1%. The haemoglobin (Hb) and Hb S levels at time of ICU admission were studied as predictors of mortality and neither showed statistical significance by Students t-test. The odds ratio, with 95% confidence intervals, was used to study other six organ supportive measures as predictors of mortality. The need for inotropic support and mechanical ventilation was a good predictor of mortality. While the need for non-invasive ventilation, haemofiltration, blood transfusions and exchange transfusions were not significant predictors of mortality. CONCLUSION Acute chest syndrome is the main cause of ICU admission in SCD patient. Unlike other supportive measures, the use of inotropic support and/or mechanical ventilation is an indicator of high mortality rate SCD patient.

Esophageal bezoar formation due to solidification of enteral feed administered through a malpositioned nasogastric tube: Case report and review of the literature

Enteral feeding is now standard and routine practice in intensive care. The use of a nasogastric tube for enteral feeding is generally considered to be safe, but tubes with small bores can sometimes lead to aspiration or passage clogging when malpositioned in sedated patients who are on long-term mechanical ventilation. Thus, accurate confirmation of correct placement is mandatory in such patients. This is not always the case, but this faulty practice can lead to serious complications in the absence of potential bezoar-forming medicines or gastrointestinal pathology. We present here one such interesting case of a patient who developed esophageal bezoar due to a malpositioned nasogastric tube for administering a casein-containing feed. In addition, we present a review of the literature.

Prevention of chronic post-surgical pain: the importance of early identification of risk factors

Chronic post-surgical pain (CPSP) is currently an inevitable surgical complication. Despite the advances in surgical techniques and the development of new modalities for pain management, CPSP can affect 15–60% of all surgical patients. The development of chronic pain represents a burden to both the patient and to the community. In order to have a meaningful impact on this debilitating condition it is essential to identify those at risk. Early identification of patients at risk will help to reduce the percentage of patients who go on to develop CPSP. Unfortunately, evidence about any effective actions to reduce this condition is limited. This review will focus on providing context to the challenging problem of CPSP. The possible role of both the surgeon and anesthesiologist in reducing the incidence of this problem will be explored.

Tourniquet application during anesthesia: “What we need to know?”

Tourniquets are routinely and safely used in limb surgeries throughout the world. Tourniquet application alters normal physiology. Healthy patients tolerate these physiological changes well, but the physiological changes may not be well-tolerated by patients with poor cardiac function. This review discusses the physiological changes associated with tourniquet use, safe practice and provides the latest updates regarding tourniquet use. A systematic literature search of PubMed, MEDLINE, ScienceDirect, and Google Scholar was done. The search results were limited to the randomized controlled trials and systemic reviews. The papers are summarized in this review.

The Dilemma of Opioid-Induced Hyperalgesia and Tolerance in Chronic Opioid Therapy

Sir, Opioids have been used for decades and continue to be used to treat severe, acute, chronic non-cancer and cancer pain.1,2 They work mainly by inhibiting spinal cord neuronal transduction and the ascending pain signals at midbrain nuclei, and through the modulation of limbic system pain perception.3 The main opioids receptors are mu and kappa receptors.1–3 The use of opioids can be challenging and not without severe or life-threatening side-effects.1,2 The World Health Organization (WHO) has recommended the adoption of a three-step analgesic ladder to meet the therapeutic challenges of administering opioids and to reduce the incidence of these side-effects. This can be achieved by starting with non-opioid analgesics followed by weak opioids with adjuvants, reserving strong opioids for cases of severe pain.2,3 When we escalate the opioid dose without getting the expected clinical response, then we may face the dilemma of tolerance, which can be defined as a decrease in pharmacologic response following repeated or prolonged drug administration. In the case of opioids, patients may experience opioid-induced hyperalgesia (OIH), which is a state of nociceptive sensitisation caused by exposure to opioids that leads to an increased response to a stimulus which is normally painful.1–4 In our practice, it is not uncommon to face this dilemma, especially during the management of patients who require long-term pain treatment with opioids.1,4 Although tolerance is faced frequently, we should not fail to recognise OIH by classifying all cases of poor response to escalating opioids as tolerance. In fact, much of the literature refers to the difficulty in differentiation between these two conditions.1,4 All patients with OIH have some sort of tolerance but the reverse is not true.1,2 Opioid-induced tolerance is rarely a limiting factor during opioid therapy in clinical practice and should not delay the start of treatment or dose escalation in patients with chronic pain.3 We should not refer to every pain-worsening during the course of therapy, as tolerance unless a detailed clinical evaluation fails to show any clear alternative cause.1,4 In OIH, the pain can become more widespread, occur in areas beyond the original pain location, and may be associated with allodynia. It occurs with various routes of administration, happening more frequently in intermittent boluses with cessation in between, than with continuous infusion.1,4 OIH is more evident with prolonged use of opioids. However, there is evidence of patients developing hyperalgesia after only short-term intraoperative opioids exposure.1,4,6 The degree or gradation of opioid tolerance is generally related to duration of exposure, daily dose requirement, and receptor association/disassociation kinetics. The mechanism of opioid-induced tolerance may include, among other things, the desensitisation to, or internalisation of opioid receptors. This is marked by a decrease in opioid binding sites that are available to provide pain relief.1–3 Another cause of tolerance is an increase in spinal cord concentrations of dynorphin, which promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids.2,3 The sensitisation of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors may play a role in opioid-induced tolerance. This is evident as NMDA-antagonists like ketamine can attenuate tolerance development and decreases in dosage, which may delay the onset of tolerance.5 The mechanism of OIH is complex and not always clear. Usually more than one mechanism is involved.4 In OIH, five possible mechanisms are involved, including activation of the central glutaminergic system; an increase in spinal dynorphins; activation of descending facilitation due to neuroplastic changes in rostroventral medulla; genetic mechanisms, and decreased reuptake of excitatory neurotransmitters and an enhanced nociceptive response. Among these five mechanisms proposed to explain OIH, the activation of NMDA-sensitive glutamate receptors is the most common possibility.1,4 Prostaglandins and cytokines might also be relevant to the development of OIH.2 As a rule, when it comes to tolerance, the increase in pain should be overcome by increasing the dose, thus providing a mode of easy diagnosis.2,3 While the diagnosis of OIH might not be straightforward, in general, if the opioids dose-reduction results in an improvement in pain control, OIH is the most likely cause. If the pain worsens, then opioid tolerance is the most likely cause.1,3,4 Quantitative sensory testing (QST), which is used to assess neurological function in chronic pain patients, can also be helpful in predicting OIH. It is performed before the initiation of opioid treatment and then repeated at certain intervals. Any changes in pain threshold upon QST can suggest OIH if other causes have been excluded.1,4 Tolerance can be treated by increasing the opioid dose. The addition of adjuvant medications like nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressant (TCA), pregabalin and others may be effective in reduction of the required opioids and delay in occurrence of tolerance.2,3 Ketamine has a dual action here as it can be used as an analgesic in low doses in addition to the NMDA antagonist effect, which can attenuate receptor sensitisation and hence, the development of tolerance.3,5 OIH treatment is much more complex and requires a specific strategy which may vary from one patient to another.1,4 This can be difficult, time-consuming ,and even impractical.1 Practically speaking, opioid reduction might induce withdrawal symptoms, which can include an increase in pain.1,4 That increase in pain will mask the clinical picture and make the differentiation more difficult.2,4 The long course of weaning which is required for those patients can cause frustration and they may give up and stop the process. This type of treatment may also require special institutes.1 Several drugs have been used to reduce the possibility of developing OIH, especially when opioid dose-reduction is not accepted or tolerated by the patient.4,6 Evidence showed that low-dose ketamine, an NMDA-receptor blocker, can modulate OIH.1,4–6 Methadone, which is a weak NMDA-receptor blocker and buprenorphine, which is a partial opioid mu agonist, can play roles in the treatment of chronic pain and OIH.1,6 Buprenorphine is an opioid partial agonist with a maximal effect which is less than that of full agonists. Buprenorphine is efficacious for longer-term opioid maintenance with a lower risk of abuse, addiction, and side effects as compared to full opioid agonists. Possible antihyperalgesics mechanisms include kappa-receptor antagonist properties and voltage-gated sodium channels blockade effects. It is an effective opioid detoxification agent with an equivalent or even better effect than methadone. Formulations for opioid detoxification treatment are in the form of sublingual tablets as they have very poor bioavailability. Transdermal patches are also available in Europe and North America for treatment of chronic pain.1,6 Other approaches may include adding NSAIDs (especially COX-2 inhibitors) as an adjuvant which may provide opioid-sparing effects in addition to modulating sensitised receptors by blocking prostaglandins.6 Anti-epileptic therapy (gabapentin or pregabalin) and α-2 receptor agonists (clonidine) can also attenuate chronic pain and reduce OIH.1,4,6 Opioid rotation is another strategy that can be used to overcome OIH.6 Finally, we can conclude that although opioids are widely used in the treatment of pain, especially chronic pain, they cannot be free of side-effects, including serious ones. OIH is one of these side-effects which may contribute to patient discomfort and carry harmful consequences if they are not diagnosed and treated. It is not uncommon to misdiagnose OIH as opioid-induced tolerance, although the treatment modalities may be different. Adding analgesic adjuvants like ketamine, COX-2 inhibitors, or gabapentinoids can reduce the required dose of opioids and attenuate both OIH and tolerance.