Putting It All Together: A General Approach to the Pharmacologic Management of Pain for Patients with Advanced CKD
A cautious stepwise approach to the introduction and titration of analgesics is outlined in Figure 3. For patients with a neuropathic component to their pain, the first step is to introduce an adjuvant. The pharmacokinetics and pharmacodynamics of recommended adjuvants in patients with advanced CKD are outlined in Table 6.
Pharmacological management of pain in patients with advanced CKD requires a cautious stepwise approach. N/A, not applicable; NSAID, nonsteroidal anti-inflammatory drug; PO, by mouth; TCAs, tricyclic antidepressants.
The pharmacokinetics of recommended adjuvants for the treatment of neuropathic in patients with advanced CKD
Anticonvulsants and tricyclic antidepressants are the two classes of drugs for which there is most evidence of efficacy. Systematic reviews have found that anticonvulsants and tricyclic antidepressants are effective in reducing neuropathic pain due to diabetic peripheral neuropathy and postherpetic neuralgia (28,29). The evidence for effectiveness for other causes of neuropathic pain is too limited to provide strong conclusions, although small studies in patients on HD have shown improvement in pain and QOL scores for diverse causes of neuropathic pain using gabapentin (30). Gabapentin is structurally similar to the neurotransmitter γ-aminobutyric acid but, rather than bind to γ-aminobutyric acid receptors, its mechanism of action is thought to be through binding to calcium channels and modulating the influx of calcium. Gabapentin is almost exclusively cleared by the kidneys and substantial dose reduction is required as the GFR declines to avoid toxicity (Table 6). Adverse effects include somnolence, dizziness, peripheral edema, and gait disturbances.
Evidence suggests that carbamazepine may be as effective as gabapentin for treating neuropathic pain in the general population and may have fewer adverse effects. Unlike gabapentin, it requires no dose adjustment in CKD as outlined in Table 6 (31). Tricyclic antidepressants are effective in the management of neuropathic pain but are less well tolerated than the gabapentinoids in patients with CKD because of anticholinergic, histaminergic, and adrenergic side effects resulting in symptoms such as dry mouth, orthostatic hypotension, and somnolence. Although dose reduction of tricyclic antidepressants is not necessarily required, patients with CKD will often respond to lower doses.
Ketamine is an anesthetic agent that functions as an analgesic in subanesthetic doses. Clinically, it is reserved for intractable neuropathic pain that is resistant to basic adjuvants and opioids. An example is the management of the pain of calciphylaxis. There is no need for dose adjustment in CKD. However, adverse events such as tachycardia and psychosis may limit its use. To reduce this risk the concurrent administration of haloperidol or midazolam is recommended (Table 6).
There are insufficient data or clinical experience with selective serotonin reuptake inhibitors and selective serotonin-norepinephrine reuptake inhibitors for neuropathic pain in CKD to make a recommendation. In the general population they tend to be less effective than anticonvulsants and tricyclic antidepressants but have fewer adverse effects (28,29).
Nonopioids should be used as initial pharmacologic management for nociceptive pain and for neuropathic pain if pain persists despite maximal tolerated dose of an adjuvant. Studies have failed to show that a weak opioid has markedly superior analgesic efficacy to acetaminophen or an NSAID.
Before starting an opioid, consider completing an assessment tool such as the Screener and Opioid Assessment for Patients with Pain–Revised to assess the risk for aberrant opioid-related behavior (32). Those that are categorized as having a high risk of future abusive drug-related behavior would benefit from referral to a pain specialist for management of their pain and opioid prescribing.
Although the initial WHO analgesic ladder advocates for trialing weak opioids before starting a strong opioid, there is no evidence that weak opioids such as codeine and tramadol are less risky than strong opioids at their lowest effective dose (Table 4) (33). The response to these weak opioids varies highly from one patient to another, with an unpredictable risk of fatal overdosing with trivial doses or poor analgesic effect after administration of standard doses (Table 4) (25). The “weak” opioids also have dose-dependent adverse effects similar to the strong opioids. A recent United States study of 140,899 patients on HD showed that the highest hazards for altered mental status, falls, and fractures among all opioids prescribed were associated with codeine (16). In addition, there is no evidence that at equivalent analgesic efficacy weak opioids carry a lower risk of addiction than low-dose strong opioids. Therefore, given the risks of using weak opioids such as codeine and tramadol in patients with advanced CKD, it seems more prudent to use to a strong opioid at a low dose with careful titration when opioid therapy is required (33).
Adverse effects of opioids are common and will prevent effective analgesia if not well managed. Constipation is persistent and nearly universal and patients should have a bowel routine, e.g., PEG 3350 prescribed pre-emptively. Nausea and vomiting occur in about 50% of people, wearing off in most after 7–10 days. The central nervous system effects occur most frequently on initiating opioids and when increasing the dose, hence the need to “start low and titrate slow.” Respiratory depression is unusual if oral, short-acting preparations are used and the dose is titrated against pain and toxicity: pain is said to be the physiologic antagonist of opioids. When pain is stable, opioids can be used in long-acting preparations such as transdermal fentanyl or methadone. As a patient’s condition deteriorates, especially nearer the end of life, swallowing becomes compromised and alternate routes are required, such as subcutaneous fentanyl. Hallucinations, a very distressing adverse effect, may occur and should be managed by dose reduction, switching to an alternative opioid, or with coadministration of haloperidol.
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