Intravenous Infusions for Refractory Cancer and Chronic Pain States




Abstract


Severe, chronic pain refractory to conventional treatments can be extremely challenging to treat. One option for these patients includes intravenous infusions. One option is lidocaine, which works via voltage-gated sodium channels for inflammatory and neuropathic conditions. Another option is ketamine, which can be used to treat CRPS, as well as a variety of other conditions. Less common infusions for chronic pain are magnesium, bisphosphonates, immunoglobulins, and phentolamine. It is important to bear in mind, however, that all these infusions have risks and side effects associated with them, which will be reviewed in the chapter.




Keywords

bisphosphonate, chronic pain, infusion, ketamine, lidocaine

 


Unrelenting, severe chronic pain is often difficult to treat, especially when it does not respond to conventional medical management. Among invasive interventions, infusion therapies have emerged as an effective treatment for refractory chronic pain when other noninvasive treatments have been exhausted. Several pharmacologic options for intravenous (IV) infusions for intractable chronic pain states are reviewed here.




Local Anesthetic (Lidocaine)


Local anesthetic infusions have been used to treat chronic pain for years. IV procaine was given to control posttraumatic pain as early as 1948. Local anesthetic drugs block sodium channels. The activation of voltage-gated sodium channels affects the pathogenesis and maintenance of both neuropathic and inflammatory pain, making local anesthetic infusions a potential therapeutic option for these conditions. Administration of high doses of lidocaine and other local anesthetics, however, may produce allergic reactions, seizure, or toxicity.


After peripheral nerve injury, neuromas and dorsal root ganglia can demonstrate increased spontaneous activity as well as increased sensitivity to chemical and mechanical stimuli. IV lidocaine indiscriminately blocks sodium channels (Na + ), an effect that may reduce neuropathic and other chronic pain conditions. It has been used as a potential treatment in many chronic pain and cancer-pain syndromes, often after other pain modalities have failed. The effectiveness of local anesthetic in chronic pain syndromes is tied to whether deafferentation is a major component of the pain.


In one study of 182 patients with various chronic pain conditions, 83 (46%) responded to IV lidocaine infusions at doses between 1 and 5 mg/kg of 1% lidocaine by infusion pump over periods up to 1 hour. Patients with radicular symptoms had the greatest response rate (75%) with relief that lasted longer than a week. Of those with peripheral neuropathies, 59% responded and 42% had some relief beyond a week. Analgesic response was not consistent in those with sympathetic mediated pain.


A systematic review of 17 randomized controlled trials compared IV lidocaine with placebo. A total of nine studies treated neuropathic pain: three cancer pain, three acute migraine, one fibromyalgia, and one myofascial pain. In nine trials, five different pain conditions were analyzed in 199 patients: peripheral nerve injury, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, and dysesthetic pain after spinal cord injury. IV lidocaine resulted in better pain relief than placebo. In another study, 11 women with fibromyalgia had 50% relief that lasted for 4–7 days. For cancer-related pain from bony metastases and for chemotherapy-induced polyneuropathy- or radiotherapy-induced plexopathy, relief with lidocaine was no different than that with saline. An electrocardiogram (ECG) was monitored continuously throughout the infusions. No arrhythmias were noted. A total of 143 lidocaine infusions were given to 134 patients. Adverse effects were experienced during 23 (16%) of the infusions; they included lightheadedness, somnolence, nausea, and perioral numbness. Unfortunately none of these studies examined the long-term efficacy of lidocaine infusions.


When complex regional pain syndrome (CRPS) was studied in 49 patients who received escalating doses of IV lidocaine over 5 days, follow-up lasted 6 months. Blood lidocaine levels were obtained daily and the infusion rate was adjusted to achieve a blood level of 5 mg/L. Infusion doses were increased only if the blood level was below the target 5 mg/L and was decreased or stopped if side effects such as arrhythmias occurred. In most patients, pain relief lasted an average of 3 months. The symptoms of mechanical and thermal allodynia were the most responsive.


IV lidocaine at 5 mg kg −1 h −1 was more effective than saline in relieving spontaneous neuropathic pain in 32 patients; however, lower doses of lidocaine were no more effective than placebo. IV lidocaine effectively lessened the pain associated with severe headache, chronic daily headache, transformed migraine, and medication overuse headache in 90% of subjects. This effect was maintained at 1 month follow-up. The most common complications were nausea, vomiting, tachycardia, or tremors, which resolved with dose reduction.


We showed a sustained reduction of neuropathic pain from central sensitization in a variety of pain conditions with IV lidocaine. We administered an initial bolus of 1 mg/kg lidocaine before an infusion of 2–4 mg/kg over 30 minutes and a recovery period of 30 minutes to 1 hour. All patients were continuously monitored with standard monitors (blood pressure, EKG, pulse oximetry, capnography) and pain scores were obtained by trained anesthesia personnel. Our protocol for outpatient lidocaine infusions is described in Table 52.1 .



TABLE 52.1

University of Chicago Protocol for Lidocaine Infusion























Consultation



  • Obtain baseline EKG and cardiac history



  • Evaluate the patient for arrhythmias before scheduling procedure

Day of Procedure



  • Assess the patient for fasting and alertness



  • Determine effects of previous infusion, if any, on




    • Pain reduction



    • Duration of effects



    • Patient function after infusion



    • Decrease in use of pain medication since infusion




  • Verify that patient has a companion to accompany him or her home



  • Obtain signature on consent form

Procedure



  • Apply standard monitors: blood pressure, EKG, pulse oximeter, capnograph



  • Start intravenous access and administer 1 mg/kg lidocaine bolus over 3–5 min



  • Follow with 4 mg/kg lidocaine (or 2–4 mg/kg) administered slowly over 30 min (or 20–30 min)



  • Record at 1, 5, 10, 15, 20, 25, and 30 min the following:




    • Time of administration



    • Blood pressure



    • Heart rate



    • Pulse oximetry



    • Pain score




  • Stop the infusion in the event of seizure activity or cardiac instability

Recovery



  • Patients recover within 30–60 min after the procedure



  • Vital signs are monitored over 15 min for a 60-min recovery period



  • At the end of the recovery period, the patient is discharged from the clinic with the accompanying caregiver

Follow-up



  • In 4 weeks, patient returns for evaluation of treatment or repeat infusion



  • The dose of lidocaine is not increased if the initial infusion was performed with 4 mg/kg over 20 min



Yet lidocaine is associated with dose-related side effects, such as tinnitus, sedation, dizziness, and, rarely, seizures and arrhythmias. The studies with IV lidocaine reviewed previously did not note any serious side effects such as seizures and arrhythmias. One limitation to IV lidocaine treatment for pain is the limited sustained benefit and impracticality of infusion as a long-term treatment. Studies are needed to prove its long-term efficacy and ideal dose.




Ketamine


Ketamine acts on both the central and peripheral nervous system and mediates multiple receptor subtypes, including opioid, N-methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainite, and gabba-aminobutyric acid (GABA)-A receptors. In chronic pain, the NMDA receptor is thought to be the main receptor mediated by ketamine. When stimulated, primarily via the neurotransmitter glutamate, up-regulation of the NMDA receptor creates central sensitization. Ketamine antagonizes the NMDA receptors. It may decrease opioid tolerance through an interaction between the receptors, the nitric oxide pathway, and μ-opioid receptors.


Ketamine has shown some analgesic efficacy in patients with CRPS, neuropathic pain, cancer pain, fibromyalgia, postherpetic neuralgia, and diabetic neuropathy. It has been most extensively studied as a treatment for CRPS. A growing body of literature supports the use of ketamine in subanesthetic doses as an analgesic. In our retrospective series, conditions that responded favorably to ketamine infusions were most commonly CRPS, intractable headache, and refractory back pain. All chronic pain conditions received analgesic benefit with ketamine for varying durations and half received benefit for 3 weeks. Side effects—including hallucination (10% of patients) and hypertension (12% of patients)—were mild and self-limited. In our pain clinic, patients who receive IV ketamine are pretreated with ondansetron 4 mg by intravenous push (IVP) and midazolam 2 mg IVP. Ketamine 0.3 mg/kg IV is then administered over 30–60 minutes. A recovery period lasts 30–90 minutes postinfusion. All patients are continuously monitored for vital signs, pain, and side effects during the infusion and in the recovery period using American Society of Anesthesiologists (ASA) standard monitors (blood pressure, pulse oximetry, EKG, capnography) by trained anesthesia personnel. Follow-up is approximately 4–6 weeks after the infusion. Depending on the pain scores, the duration of pain relief and the occurrence of side effects, the dose is increased, maintained, or discontinued. Table 52.2 summarizes our clinic’s protocol for outpatient ketamine infusions.



TABLE 52.2

University of Chicago Protocol for Ketamine Infusion























Consultation



  • Obtain baseline EKG and cardiac history



  • Evaluate the patient for arrhythmias before scheduling procedure

Day of Procedure



  • Assess the patient for fasting and alertness



  • Determine effects of previous infusion, if any, on




    • Pain reduction



    • Duration of effects



    • Patient function after infusion



    • Decrease in use of pain medication since infusion




  • Verify that patient has a companion to accompany him or her home



  • Obtain signature on consent form

Procedure



  • Apply standard monitors: blood pressure, EKG, pulse oximeter, capnograph



  • Start intravenous (IV) access and pretreat with




    • Midazolam 2 mg IV



    • Ondansetron 4 mg IV




  • Begin ketamine infusion with 0.3 mg/kg in 100-mL bag for 30–45 min



  • Record at 1, 5, 10, 15, 20, 25, and 30 min the following:




    • Time of administration



    • Blood pressure



    • Heart rate



    • Pulse oximetry



    • Pain score




  • Depending on the patient’s vital signs and pain scores, the infusion may be extended to 60 min



  • Stop the infusion in the event of any of the following adverse effects:




    • Hallucinations



    • Blood pressure increase >20% of baseline



    • Severe anxiety



    • Nausea



    • Unmanageable, symptomatic nystagmus




  • Most adverse effects disappear when infusion is stopped



  • Assess the patient for urgent management

Recovery



  • Patients recover within 30–60 min after the procedure



  • Vital signs are monitored every 5–15 min for 60 min during recovery or more frequently if needed



  • At the end of the recovery period, the patient is discharged with accompanying caregiver

Follow-up



  • In 4 weeks, patient returns for evaluation of treatment or repeat infusion



  • Infusion doses may be increased to 0.6–1 mg/kg depending on the effect of the infusion on pain scores and patient function or satisfaction with pain relief

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Sep 21, 2019 | Posted by in PAIN MEDICINE | Comments Off on Intravenous Infusions for Refractory Cancer and Chronic Pain States

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