Managing Comorbid Disorders Patients should have psychiatric disorders and psychological symptoms managed in the context of multidisciplinary care. Benzodiazepines may be helpful as second-line agents when used short term to treat anxiety that arises with pain from injury or hospitalization; however, benzodiazepines are best avoided for long-term use because of their addictive potential, the increased risk for overdose, respiratory depression, and death when co- prescribed with opioids, and the blunting of cognitive and, therefore, coping skills in patients with chronic pain. 3 In 2016, the FDA announced the requirement of boxed warnings with information about serious risks of extreme sleepiness, respiratory depression, coma, and death associated with combining prescription opioids and benzodiazepines. 71 For chronic mental-health disorders, a combination of medications indicated for the specific condition plus evidence-based psychotherapy, such as CBT, are recommended. 3 SSRIs and SNRIs (and sometimes buspirone) are medications most frequently used for generalized anxiety disorder, which often accompanies chronic pain. 3 Tricyclic antidepressants are sometimes used for panic disorder, but SSRIs, because of their lower side effect profile, are generally considered safest and most effective. 3 Recommended medications for PTSD include venlafaxine ER and prazosin. 3 When comorbid anxiety disorders are severe, psychiatric consultation to establish medication regimen is recommended. 3 In milder cases, no medication may be necessary if adequate behavioral and other nonpharmacologic treatments are helpful. In general, opioid therapy in patients with untreated OUD is unlikely to achieve therapeutic aims, and initiating it is not recommended. 23 HCPs may consider or continue opioids for patients with chronic pain and histories of drug abuse and psychiatric issues only if they are able to implement more frequent and stringent monitoring parameters. 64 In such situations, HCPs should strongly consider consultation and co-management with a pain, mental-health, or addiction specialist or else refer the patient for specialist management. 64,78 Prescription of opioids may not be appropriate until the comorbidity has been addressed. 78 For patients exhibiting active OUD who are already on opioids, oftentimes at high doses, HCPs should provide or refer for addiction management and treatment with medications such as buprenorphine or methadone via an opioid treatment program. 73 Treatment of pain with full agonist opioids in patients with OUD would need a careful evaluation of the risks versus benefits to determine management. It is unlikely that a patient with OUD and pain will have adequate pain control in the absence of treatment of OUD. 23 Taper of opioids may be considered in addition to initiation of OUD treatment. Sudden discontinuation or tapering of opioids in the absence of treatment of OUD with buprenorphine or methadone will put patients with OUD at risk for serious adverse outcomes
(see subsequent sections on tapering opioids and managing OUD). 18,19,73 Dosing and Titration Considerations Opioids are best when used at the lowest effective dose and combined with nonmedication and/or nonopioid medication modalities of treatment. 64,78 When opioids are initiated, the goal is to select the lowest effective dose for shortest duration possible to achieve therapeutic goals. 22,64 The risk of overdose increases with the dose, but the therapeutic window varies considerably from patient to patient. Various opioid products, delivery systems, and formulations are available to maximize analgesia and minimize or prevent adverse effects. For outpatient chronic pain management, opioids are typically administrated through the oral, transmucosal, and transdermal routes. Each medication has advantages and disadvantages and safety concerns, some of which are intrinsic to all opioids and some of which are specific to the route or formulation. In pain management, IR/SA opioids, are indicated for pain severe enough to need opioid treatment and for which non-opioid treatments are ineffective or not tolerated. 70 These short-acting opioids are preferred and considered safer when initiating a therapeutic trial of opioids and are often prescribed for use as needed every 4 to 6 hours. 70,78 Commonly prescribed IR/SA opioids include morphine, hydromorphone, oxymorphone, codeine, fentanyl, hydrocodone, and oxycodone. 135 Codeine, hydrocodone, and oxycodone are also available in combination with ACET or an NSAID, which limit daily dose due to risk for liver and GI toxic effects. 135 Patients with no or limited exposure to opioids should be initiated at the lowest available dose and titrated slowly to minimize adverse effects. 78 Dual-mechanism opioids may control pain with less opioid, and opioid-sparing techniques, such as combining therapeutics should be considered. If patients require long-term maintenance and pain is severe enough to require around-the-clock analgesia that is not adequately relieved by IR/SA opioids or other therapies, consider a transition to ER/LA opioids with scheduled dosing. 136 ER/LA opioids are primarily intended to be taken once or twice a day, are not indicated for acute pain, and are for use only in patients who are already tolerant to opioids. 69 It is critical also that HCPs be aware that all transdermal and transmucosal fentanyl and hydromorphone ER products are for use only in opioid-tolerant patients and never for acute or short-term pain. 69 Adult patients are considered opioid tolerant if they have received the following dosages of opioids (or equianalgesic dosages of other opioids) for at least one week: 64,69 • 60 mg daily of oral morphine • 25 mcg per hour of transdermal fentanyl • 30 mg daily of oral oxycodone
Product information for individual formulations contain guidance on degree of opioid tolerance necessary for administration and minimum titration intervals. IR/SA opioids are sometimes used for severe exacerbations of pain (i.e., “breakthrough pain”) that occur against a background of chronic pain that is being treated with ER/LA opioids. This practice has support but is controversial in chronic noncancer pain, because the rapid-onset medications used as rescue medications may increase risk for misuse. 78 Because patient response varies, titrating to a therapeutic dose should be individualized with close attention to efficacy, tolerability, and presence of adverse effects. The CDC recommends reassessing risk versus benefit at ≥50 MME per day, avoiding increasing dosages to ≥90 MME per day, or carefully considering the rationale. 64 Authors of the CDC guideline subsequently clarified that the guideline does not support sudden dismissal of patients or hard limits on dosage and treatment durations. 18 These circumstances particularly affect patients who are already receiving long-term opioid therapy and who seek continuation of care after losing access elsewhere. 137 It must be reemphasized that recommended threshold doses do not remove the necessity of exercising caution at any dose or the importance of individualizing the dose. Particular care is essential, not only during opioid dose initiation but also whenever doses are increased, changed to a different opioid, or when CNS-depressant medications are added to the regimen. Patients should be monitored carefully, particularly within 24 to 72 hours of opioid initiation or upward titration. Studies show that patients are particularly vulnerable to respiratory depression at these times. 119,120 HCPs should consider opioid initiation a trial, discuss with the patient the risks and benefits of continuing opioid therapy beyond 90 days,19 and, if opioids are continued, reevaluate the treatment plan at least every three months. Patients who require repeated dose escalations to achieve sufficient pain relief should be reevaluated for the cause, and the risk-to-harm benefit of long-term opioid therapy should be reconsidered. 78 Self-Assessment Question 8 Which dosage of transdermal fentanyl administered for a week would an adult patient be considered opioid tolerant?
a. 25 mcg per hour b. 50 mcg per hour c. 75 mcg per hour d. 100 mcg per hour
The correct answer is a. Rationale : Adult patients are considered opioid tolerant if they have received 25 mcg per hour of transdermal fentanyl for at least one week.
• 8 mg daily of oral hydromorphone • 25 mg daily of oral oxymorphone
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