Pharmacological Pain Treatment in Older Persons

Tramadol has a dual mechanism of action that explains its efficacy against neuropathic and nociplastic/functional pain: transformation into an active metabolite O-desmethyltramadol with an agonist effect on µ-opioid receptors, and inhibition of the reuptake of serotonin and norepinephrine by the parent molecule. Due to its complex mechanism of action tramadol can be considered a first-line treatment for mixed pain (neuropathic and nociceptive) [100, 101], but combinations with anti-depressants that increase the risk of serotonin syndrome must be avoided.

Side-effects such as nausea, vomiting, constipation (however, usually less intense than with codeine and strong opioids), reduction in seizure threshold (with an increased risk of seizures) and higher incidence of confusion and of delirium are well documented in older persons [102]. Combination with other serotoninergic drugs (anti-depressants, particularly SSRIs or MAOI such as selegiline, linezolid, lithium and dextromethorphan) or strong CYP2D6 inhibitors (paroxetine and fluoxetine) should be avoided, as this increases the risk of falls and serotonin syndrome. In addition to serious neuropsychiatric and gastrointestinal adverse events, hepatic and metabolic effects have been reported. Hypoglycaemia, increased anti-coagulant effect and hyponatremia are now well recognised problems with tramadol [103‐105]. Close monitoring of serum electrolytes and International Normalized Ratio (INR) are, therefore, essential during the initiation and dose escalation of tramadol therapy in older persons. Tramadol should be used with caution in persons with weak to moderate renal and liver impairment and avoided in individuals with severe renal and liver impairment.

While fixed dose tablets may not be adequate, the oral solution (sometimes presented as a paediatric formulation with 10 drops corresponding to 25 mg) allows better individualised oral titration, as recommended by experts [13, 106, 107]. Titration should start between 12.5 mg and 25 mg every 4–8 h, depending on age, weight and kidney function. The progressive increase in tramadol dose should occur every 48–72 h, as needed. Good tolerance of tramadol allows a switch to the lowest sustained release form, while allowing additional doses of oral solution (10–20% of daily dose) to be taken up to three times a day if needed. The use of the oral solution at home may be limited in older people with cognitive impairment because of the need to precisely measure the dose to be helped by a caregiver. It is, therefore, essential to ensure that it is dispensed safely. The injectable form of tramadol also makes possible to administer tramadol subcutaneously as injections or by pump. The equivalence between oral and injectable dosages is not well known, but in practice, oral titration and maintenance therapy are applicable to the injectable form of tramadol.

In patients aged 75 years or older, the pharmacokinetics of tramadol changes [108], the bioavailability of O-desmethyl-tramadol (but not tramadol) increases by 35% compared with patients under 40 years of age and its elimination half-life doubles [109]. Therefore, for safety reasons, it is recommended that dosing of tramadol in older people should be adapted to renal function and not exceed a maximum dose of 300 mg per day from the age of 75 years or 200 mg in co-morbid patients [110]. Tramadol is also used combined to paracetamol to improve analgesia and avoid escalation of tramadol doses, thus limiting tramadol induced side effects [111‐113]. Finally, tramadol is commercialised in fixed combinations with dexketoprofen in some countries [114]. Limited data are available in patients over 75 years, and fixed dose combination of tramadol 75 mg + dexketoprofen 25 mg should be used with caution in these patients, because of the increased frequency of adverse reactions to NSAIDs in older patients.

Codeine is used both for pain and cough and its analgesic activity is associated to its metabolism via CYP2D6 to morphine (5–10% of dose). In Caucasian populations, 8–10% of people are poor metabolisers; however, 3–5% are ultrarapid metabolisers [115]. Those who are ultrarapid metabolisers (carriers of the CYP2D6 gene duplication) have significantly higher levels of morphine and morphine metabolites after the same dose of codeine [116]. Its anti-tussive effect should be acknowledged, particularly in chronic lung disease frequently encountered in older people.

In practice, the multiplicity of formulations containing both codeine and paracetamol with variable dosages stresses that particular attention must be paid to prescribing, specifying the desired dose of codeine. The lowest available dose varies according to countries (8 mg in Ireland and the United Kingdom and 20 mg or less in other countries). A dose of 16–20 mg codeine, taken every 4–8 h, is usually the initial dose in older people; it is commonly combined with 500 mg of paracetamol. The dosage can be increased to 30 mg of codeine per dose, bearing in mind that the maximum dose is 180 mg per day (240 mg/day in the United Kingdom). The effectiveness of codeine in the treatment of pain in older persons has been shown [117]. The sustained release form of dihydrocodeine is a worthwhile alternative to repeated codeine dosages after titration.

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine, used as an analgesic and anti-tussive agent and for the management of dyspnoea and opioid addiction. Limited data are available on the potency of DHC compared with other opioids. The analgesic effect of DHC is similar to codeine and approximately twice as potent as tramadol for an oral route. In contrast to codeine and tramadol, DHC analgesia seems to be irrespective of CYP2D6 activity [118]. The sustained release form of dihydrocodeine is an interesting alternative to repeated codeine and DHC intakes after titration. The usual starting dose of DHC sustained release is 60 mg every 12 h and may be increased to a maximum of 120 mg every 12 h.

Codeine and dihydrocodeine should not be used in patients with liver impairment due to unpredictable pharmacokinetics and used with caution in patients with renal insufficiency.

Recommendations

Morphine is a pure mu-opioid receptor agonist. The age effect results in a higher circulating blood concentration of the parent drug and active metabolites and slower elimination in older people compared with younger people at the same dose. It is, therefore, necessary to adjust the dose of morphine by titration of small doses of sustained-release morphine (10–20 mg/day) for a baseline dose and immediate-release morphine for acute exacerbations. Alternatively, immediate release preparations can be administered regularly every 4–8 h (starting with 2.5 mg), with additional doses as required. Doses need to be lower and intervals between doses adjusted in patients with renal impairment due to the risk of accumulation of active morphine metabolites (morphine-6-glucuronides and morphine-3-glucuronides, the latter having neurotoxic properties).

IV morphine is used to relieve acute pain or severe exacerbation of chronic pain in emergency units and in in-patient settings. Titration needs to be cautious with subsequent boluses of 1–2 mg administered every 10–15 min. Subcutaneous (SC) morphine is an alternative used mostly in palliative care patients with difficulty swallowing. Due to low bioavailability of oral morphine, SC doses need to be reduced to about a third of oral doses. Intervals between subsequent SC doses are 4–8 h, the latter when morphine elimination is slowed; SC continuous infusion may also be used.

Studies show good efficacy and relatively good tolerance of treatment with morphine in older patients. An international consensus statement and review [85] showed that older persons with chronic severe pain respond, as well as or even better, to morphine than younger age groups and suggested the need to address the problems with under prescribing in older persons. It is important to ensure safe morphine prescribing in older persons with chronic kidney disease, a common comorbidity, as there is evidence that accumulation of active metabolites can lead to opioid toxicity [110], and caution is mandatory in the frail elderly [120].

Hydromorphone has pharmacokinetic properties comparable with those of morphine and is used mainly in the context of opioid rotation.

When given orally, this pure µ- and κ-opioid receptor agonist is 50% more potent than morphine. Its renal elimination justifies, as with morphine, a progressive dosage reduction in older people. Ten percent of oxycodone is converted by CYP2D6 to active oxymorphone that may accumulate when renal function is decreased. Initial doses of sustained release preparations administered twice daily in older people are recommended. Immediate release preparations can be used on a regular base or as rescues. Combined formulations of oxycodone and naloxone prolonged-release tablets are available for patients with opioid-induced constipation. These formulations need to be used with caution in older people and individuals with renal impairment and are contraindicated in moderate and severe hepatic impairment (due to the risk of the increased naloxone bioavailability and its potential antagonizing effect on opioid analgesia). Studies with oxycodone in older persons have been reviewed [117].

Fentanyl is a pure µ-opioid agonist used in acute (IV) and chronic pain management for baseline (transdermal formulation) and breakthrough pain (transmucosal formulations). Transdermal fentanyl is usually highly effective and less constipating than morphine and oxycodone. Due to high potency, its commencement and further titration need to be extremely cautious. Transdermal fentanyl is never recommended for initiating a strong opioid both in young and older people [4]. Its use should be proceeded with dose titration with immediate release opioid (usually morphine). Long delay in reaching a steady state does not make fentanyl a first-choice drug in the titration phase of analgesic treatment. The lowest dose patch (12 µg/h) is already equivalent to 30–45 mg/day oral morphine. Greater variations in the transcutaneous absorption in older persons makes it more difficult to anticipate its bioavailability [85]. Due to its high lipid solubility, fentanyl is eliminated more slowly in older people but is the opioid of choice in renal failure and for individuals on dialysis [110].

Transmucosal (buccal, sublingual and intranasal) fentanyl has a marketing authorisation for breakthrough pain in cancer in adults. Formulations with a very short onset of action (5–15 min) are useful in pain exacerbations, but prescribers should be aware that xerostomia, frequent in older people, can affect fentanyl absorption and effect. A strong consensus was achieved regarding which pharmacological treatment (transmucosal fentanyl) and dosing method (start low and go slow) are the most suitable for the older population suffering from breakthrough cancer pain [121].

Buprenorphine is a partial agonist at µ-opioid receptor and a κ- and δ-opioid antagonist [122]. It is available in sublingual tablets and transdermal formulations but not authorised in all European countries in the context of pain. The recommended starting dose for non-cancer pain is 0.1–0.2 mg every 8 h in transmucosal tablets and 5–17 µg/h in transdermal patches (equivalent to approximately 10–30 mg of oral morphine per day). Buprenorphine is usually well tolerated, with lower respiratory depressant risk, and is less likely to cause cognitive impairment than other opioids [122‐126]. It can also be recommended for renal impairment or in patients having dialysis [127]. In older persons, the risk of falls and subsequent fractures induced by opioids should be taken into clinical consideration, but buprenorphine presents a lower risk than tramadol and other strong opioids [117, 128, 129].

Methadone is a combined µ-opioid agonist and NMDA receptor antagonist, with a long and variable half-life (8.5–120 h) that makes it risky to introduce and dose adjust in older people, particularly in patients on dialysis. Due to the lack of active metabolites it can be used in people with renal impairment, including dialyzed patients [127]. It is a substrate of CYP450 (mainly CYP2B6 and CYP3A4), susceptible to drug interactions when combined with inhibitors or inducers of the metabolizing enzymes [130]. The possibility of prolonged QT interval with potentially serious ventricular dysrhythmias is significant and requires regular cardiac assessment (ECG and electrolytes level) [131]. It is mainly used in palliative care and reserved for physicians experienced in pain management.

Tapentadol is a synthetic opioid, not available in all European countries, with a dual mechanism of action of µ-opioid receptor agonism and noradrenaline reuptake inhibition. It has a low risk of drug interactions, due to reduced plasma protein binding, predominant metabolism by glucuronidation and lack of impact on CYP450 enzymes [132, 133]. It is effective and well tolerated in older patients suffering from musculoskeletal pain, but because of limited data, there is insufficient evidence to support the use of tapentadol over other opioids [134, 135].

Nalbuphine is a µ-opioid receptor antagonist and κ-opioid agonist. It is available in injectable formulation only and used post-operatively or in emergency departments for acute pain but never in chronic pain due to its antagonist action at µ-opioid receptors. Nalbuphine requires hepatic metabolism and renal elimination; it is necessary to adjust dosage to impaired liver and kidney function. The evidence of nalbuphine in older patients is very sparse. Single studies showed, that in intensive care pain management, in patients over the age of 60, nalbuphine has worse analgesia than sufentanil [136]. The authors recommend that because of altered pharmacokinetics and clearance in older, debilitated or cachectic patients, caution should be used when administering nalbuphine to these patients because life-threatening respiratory depression can result [137].

Side effects are similar in older people as in younger adults, and their incidence is limited by applying best practice guidelines for older persons. Constipation is common [138] and often already present before the opioid is prescribed. Laxatives acting through different mechanisms (starting preferably with osmotic agents, e.g. lactulose or macrogols) should be used or increased as soon as the opioid is introduced in addition to the recommendations for diet and hydration. Use of oxycodone/naloxone preparations may be considered in some patients. Bowel function in patients on chronic opioid therapy need to be closely monitored. Nausea and vomiting may occur with an initiation of an opioid but usually disappear after a few days of regular daily treatment. Nausea may be relieved for example by low doses of metoclopramide or haloperidol. Care must be taken to prevent dehydration, as older people may not always feel thirsty due to lower age-associated osmoreceptor sensitivity and, consequently, may not drink sufficiently. Drowsiness, often increased by the co-prescription of other potentially sedative drugs (benzodiazepines, hypnotics such as zolpidem, zopiclone and zaleplon), requires an adjustment of opioid dosage. If it appears during treatment, kidney function should be checked. Urinary retention is more likely if the patient has marked constipation or prostatic hyperplasia. Confusion linked to opioids must be well documented as urinary retention, electrolyte/metabolic disorders, dehydration, inappropriate sedative or psychotropic medication and unrelieved pain may also be a cause of confusion. Falls and fractures are a major concern as evidence indicates that older patients using opioids are at higher risk of falls and fractures, with a highest risk in the first two weeks after opioid initiation. Closer monitoring particularly in the first weeks of opioid therapy and education of the patient’s family need to be undertaken [139, 140].

Multiple potentially serious drug interactions may occur, and several are to be noted. Sedation and central nervous system depressant effects have a risk of respiratory depression [141] when an opioid analgesic is combined with other CNS depressant drugs, benzodiazepines and drugs that inhibit opioid metabolism, primarily CYP3A4 inhibitors, (e.g. clarithromycin or voriconazole and other anti-fungal azoles), which may markedly inhibit metabolism of oxycodone, fentanyl and methadone, as well as buprenorphine to a lesser extent). Failure of analgesia in patients who receive an opioid analgesic (µ-opioid agonist) concurrently with an antagonist at µ-opioid receptors (e.g. nalbuphine) erroneously or with a drug that induces opioid metabolism (e.g. carbamazepine, rifampicin or enzalutamide). 3/Serotonin syndrome when an opioid (especially tramadol) is combined with another drug with serotoninergic activity (e.g. SSRIs, linezolid or MAO inhibitors) or with a drug that inhibits CYP2D6 (for example, paroxetine or fluoxetine). Ventricular arrhythmia (including torsade de pointes) may arise from co-administration of methadone with another drug that prolongs the QT interval (e.g. citalopram or sertraline). Reduced anti-platelet effect of oral P2Y12 inhibitors (e.g. clopidogrel and ticlopidine) when co-administered with morphine.