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Providing effective analgesia to a patient may seem routine, yet it is one of medicine’s most satisfying achievements. Serious pain eventually afflicts virtually everyone, and is particularly prevalent in the elderly. Currently available analgesics control acute pain promptly and safely in the vast majority of patients. Unfortunately chronic pain typically presents a much more difficult challenge. In a recent systematic review, the prevalence of pain in older people ranged from 62 to 83%, the most common type being musculoskeletal.1
This Letter focuses on the evidence and principles for drug therapy of chronic non-malignant pain in the older person.
Surprisingly few clinical trials provide guidance on how best to treat pain
in older people.1 Recent Clinical Practice
Guidelines2,3 are
substantially opinion-based. They reiterate the familiar adage, "start low
and go slow", and also support use of opioids in the elderly for both
malignant and non-malignant pain. These guidelines also suggest that a
combination of drugs at low dose may be safer than increasing the dose of a
single agent. However they offer no controlled trial data to support this
approach, and it is possible that interactions between multiple drugs at low
dose may be more dangerous than higher doses of a single drug.
Interpreting clinical trials of analgesics is especially difficult because side
effects often compromise blinding. For example, a patient may interpret sedation
as pain relief, without appreciating the risks of impairment as regards driving,
falls, or mental function.
Older trials, while often of poor quality, tended to report more useful clinical
endpoints, such as ‘patient improved or did not’. More recent trials report
average pain scores, which don’t allow calculation of what proportion of
patients have clinically significant pain relief.
Insufficient evidence about a drug is less critical in managing pain and
other symptoms than when prescribing preventive therapy. The randomized
controlled trial (RCT) evidence tells us that for most analgesics, only a
minority of patients with chronic pain will respond. It is therefore up to the
physician to establish that the therapy is in fact helping each individual
patient. This can be achieved with a short therapeutic trial (usually 2 weeks).
If the patient’s pain or suffering are not substantially reduced, or if the
side effects outweigh the benefit, then the therapy should be stopped. Even when
the therapy is judged to be helpful, it is still necessary to reassess efficacy
at regular intervals (say every 3 to 6 months) by stopping it altogether. Ultimately
improvement in function is the real goal of therapy.
Most long-term therapies have some risks (such as falls with tricyclic and SSRI
antidepressants, or GI hemorrhage with NSAIDs), and as a consequence,
practitioners must continually balance the symptomatic and functional benefit
against these risks.
The fact remains that long-term RCTs are needed in the elderly to measure
serious adverse outcomes and provide physicians with better tools to calculate
the benefit-harm ratio in individual patients.
Normal aging and associated organ dysfunction tend to increase sensitivity to both desirable and adverse effects of most drugs. Reduced renal function (even with "normal" serum creatinine), altered volume of distribution and a range of other factors all potentially increase elimination half-life and drug effect for many drugs. These features support the "start low and go slow" approach.
We have reviewed the published literature on selected drugs, using standard search techniques to identify reports of double-blind RCTs. When choosing drugs for a therapeutic trial in chronic pain, it may be useful to classify patients as having either non-neuropathic or neuropathic pain.
NON-NEUROPATHIC PAIN
Methocarbamol (Robaxin®) including various formulations combined with acetaminophen, ASA, and codeine (e.g. Robaxacet-8®, Robaxisal-C®) have been available for decades. However we could find no well-controlled blinded studies that establish its efficacy. Methocarbamol has a short elimination half-life (2 hrs) and has significant side effects, including drowsiness, dizziness, and nausea in 4-5% of patients. The drug’s popularity may be due to its sedative effect, or more likely to the effect of the other ingredients in combination tablets. Generic acetaminophen+/-codeine affords a less expensive and safer choice. (see Table)
Cyclobenzaprine (Flexeril®) like other tricyclics, has a complex route of metabolism. Elimination half-life is 1-3 days, and hence it can be given as a single bedtime dose. It has significant potential for many drug interactions, however, and side effects such as drowsiness, dry mouth and dizziness are common. Constipation, urinary retention, delirium or dysrhythmias may occur, particularly in older patients. The manufacturer does not recommend use of cyclobenzaprine for periods longer than 2 to 3 weeks. Only one RCT of reasonable size and duration has examined efficacy.4 This was a Canadian study of 208 patients with fibromyalgia, which compared cyclobenzaprine (10-30 mg/d) with amitriptyline (10-50 mg/d) or placebo. At 1 month, 12% of cyclobenzaprine-treated patients and 21% of those taking amitriptyline showed improvement as compared with placebo. Most patients experienced side effects, and at 6 months neither drug provided any significant benefit.
Benzodiazepines (diazepam, lorazepam, clonazepam, etc.) are not analgesics and can potentiate the sedative side effects of other analgesics. Because of their potential to induce dependence, they are not indicated for chronic pain.
Tricyclics such as amitriptyline,
imipramine, and their metabolites nortriptyline and desipramine are widely used
in chronic pain. They share anticholinergic side effects (constipation, dry
mouth, urinary retention, delirium), sedation, weight gain and a propensity to
fall. Average elimination half-live is long (1 day) and is greatly prolonged in
genetically poor metabolizers (about 5% of people), in whom accumulation can
occur well past one week at any dose.
For chronic back pain, a 1997 systematic review found no evidence that
antidepressants are superior to placebo.5 For
other conditions, the evidence is mixed. In 41 patients with chronic
non-malignant pain, amitriptyline at 25 mg/d was better than placebo within the
first week.6
Overall, the published trials suggest that a minority of non-depressed
patients with chronic pain attain a modest benefit.7
This benefit must be weighed against the side effects listed above.8
Evening dosing may improve the benefit-harm ratio for sedation. There is little
evidence to support large doses. If pain is not clearly improved within a week
at a low dose, titrate by doubling the dose. A considered decision either to
stop or to continue a tricyclic should be made within the first month of
therapy.
SSRIs. Clinical trials in headache, neuropathy, and fibromyalgia have produced conflicting results but on balance the trial data is not convincing that SSRI’s are useful for analgesia.
Acetaminophen remains the analgesic of first choice for mild to moderate non-neuropathic pain. No conventional NSAID has proved better than any other in managing the pain of osteoarthritis (see Letter #4). Cox-2 inhibitors will be the subjects of a Letter later this year.
At present there is no conclusive RCT evidence that glucosamine is effective in osteoarthritis.9
The only phenothiazine with analgesic properties, methotrimeprazine also has prominent sedative, anticholinergic, and hypotensive effects. These adverse effects may be tolerable in the short term, but likely outweigh its advantages in most long-term therapy. Like other phenothiazines it has a long half-life and a risk of extrapyramidal symptoms, including tardive dyskinesia.
Sir William Osler presumably drew on clinical experience when he acclaimed morphine as "God’s own medicine". Even so, there is surprisingly little evidence from controlled trials to guide the use of opioids for chronic non-malignant pain.2 Standard recommendations favouring codeine/morphine over alternative opioids are not evidence-based. At higher cost, controlled-release formulations offer convenience of dosing and more consistent analgesia. Experience suggests that constipation can be addressed with diet, improved mobility, and laxatives, although controlled trials in this area are non-existent. Oral anileridine (Leritine®) and transcutaneous fentanyl (both analogs of meperidine) are occasionally useful in morphine-intolerant patients. Meperidine (Demerol®) has poor oral bio-availability and a short half-life. Normeperidine, a metabolite of both meperidine and anileridine, has a much longer elimination half-life than the parent drugs, and may also cause life-threatening convulsions, especially during chronic high dose therapy, or in patients with renal insufficiency associated with aging. Morphine and congeners are therefore preferable.
Patient and prescriber misconceptions about the "addictive potential" may result in under-use of opioids for chronic pain in the elderly. It is true that continuous chronic use is likely to induce pharmacologic tolerance and dependence, but is however unlikely to cause the destructive pattern of behaviour termed "addiction". As in the control of cancer pain, a decision to employ opioids should weigh the potential benefits of analgesia and improved function against the well-known side effects of constipation, nausea, sedation, and mental clouding. Concomitant use of anticholinergic and CNS-depressant drugs (including antispasmodics, antihistamines, tricyclics, benzodiazepines, and antipsychotics) should be minimized. As with other drugs, opioid therapy should be continued only if symptoms and/or function clearly improve during a therapeutic trial.NEUROPATHIC PAIN
Amitriptyline and desipramine were associated in a small trial with moderate or better pain relief in 74% and 61% of patients with painful diabetic neuropathy as compared with 41% of patients on placebo. Fluoxetine was similar to placebo.10 The number needed to treat (NNT) for amitriptyline and desipramine is 3 and 5, respectively.
Carbamazepine, although widely used for chronic neuropathic pain, has limited RCT evidence for efficacy. Combining 3 placebo-controlled trials in trigeminal neuralgia yields a 2-week NNT of 2.6 for benefit, and a NNH of 3.4 for adverse effects (mainly drowsiness, dizziness and gait disturbance) over two weeks. Doses were mostly 400-1000 mg/day. A 30-person cross-over trial with carbamazepine in diabetic neuropathy suggests a modest benefit within 2 weeks at doses 600 mg/day or less.11 Carbamazepine risks many interactions and toxicities of particular significance in the elderly (sedation, ataxia, hyponatremia, leukopenia). Its elimination half-life is about 12 hours. If improvement is not obvious within 2 weeks, the drug should be discontinued to avoid toxicity.
Gabapentin (Neurontin®) is an
anticonvulsant of unknown mechanism, excreted unmetabolized by the kidney. The
average 6-hour elimination half-life measured in young volunteers is prolonged
in older people with diminished renal function. Although gabapentin has been
widely employed in various types of chronic pain, little evidence from
high-quality controlled trials is available. A recent 8-week double blind
RCT (N=165) compared gabapentin with placebo in otherwise uncomplicated patients
with painful diabetic neuropathy.12 At
1,800 mg/d, a small benefit (1 point decrease on an 11 point pain score) was
noted within 2 weeks. Benefit did not increase at higher doses, nor with longer
therapy. The chance that a patient could discern a "moderate or
marked" benefit attributable to gabapentin in an overall self-rating was
27% (NNT=4). The statistical validity of this number is questionable, and
adverse effects such as dizziness (ARI=19%, NNH=5) and somnolence (ARI=16%, NNH=6)
were frequent.
A similar 8-week RCT (N=229) in patients with post-herpetic neuralgia
found a slightly larger average change in score (2/11 points) favouring
gabapentin.13 Again, the benefit was seen by 2
weeks at 1,800 mg/d. Somnolence (ARI=22%, NNH=5), dizziness (ARI=19%, NNH=5),
and ataxia (ARI=7%, NNH=14) were common.
A small crossover RCT (N=19) compared gabapentin (900- 1,800 mg/d) with
amitriptyline (25-75 mg/d) for diabetic neuropathy. Amitriptyline provided
"moderate, a lot, or complete" pain relief in 67% of patients, vs. 52%
of those on gabapentin (P < 0.01). Virtually all patients experienced adverse
effects with each drug.14 Gabapentin benefits at
best a minority of patients with painful diabetic or post-herpetic neuropathy.
Toxicity, but not analgesia, is dose-dependent. Stop the drug if pain relief
does not clearly outweigh harm by 2 weeks.
TABLE:
Common analgesics and doses for chronic pain in the elderly.
| Drug | Starting dose | Usual maximum dose | Daily cost* |
| Methocarbamol/ASA/C1/2 | 1 tab bid | 2 tabs qid | $1.25 - 5.00 |
| Acetaminophen/C1/2 | 1 tab bid | 2 tabs qid | $0.06 - 0.24 |
| Cyclobenzaprine | 10 mg hs | 30 mg hs | $0.38 - 1.15 |
| Amitriptyline | 10 mg hs | 75 mg hs | $0.01 - 0.03 |
| Desipramine | 10 mg hs | 75 mg hs | $0.19 - 0.78 |
| Imipramine | 10 mg hs | 75 mg hs | $0.01 - 0.04 |
| Nortriptyline | 10 mg hs | 75 mg hs | $0.14 - 0.81 |
| Methotrimeprazine | 2 mg hs | 25 mg hs | $0.06 - 0.12 |
| SR morphine | 10 mg bid | 60 mg bid | $0.70 - 2.56 |
| Carbamazepine | 100 mg bid | 400 mg bid | $0.24 - 0.96 |
| Gabapentin | 300 mg bid | 600 mg tid | $2.08 - 6.24 |
| Mexilitine | 100 mg bid | 200 mg tid | $0.76 - 1.50 |
| This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to October, 1999. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 75 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians. |
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©Therapeutics Initiative. Last updated: February 9, 2000.