Ms. Wick is a senior clinical research
pharmacist at the National Cancer
Institute, National Institutes of
Health, Bethesda, Maryland. The
views expressed are those of the
author and not those of any government
Pain has received a considerable
amount of attention since
the Joint Commission encouraged
health care providers to consider
it the fifth vital sign. Treating acute
pain is quite straightforward. When pain
becomes chronic, providing optimal pain
management requires a fine balance
between the patient's needs and beliefs,
analgesic availability, clinician skill, and
Most pharmacists are familiar with the
World Health Organization's pain ladder,
which indicates that mild pain should be
treated with OTC drugs or prescription-strength
drugs (NSAIDs) with or without adjuvant
treatments (antidepressants, anticonvulsants,
etc). If pain is of moderate
intensity, stepping up to an opioid suitable
for moderate pain, with or without
analgesic and adjuvants,
is appropriate. The final step—severe
pain—is treated with the strongest of
the opioids, again, with or without additional
or adjuvant treatments.
Clinicians should schedule round-the-clock
analgesics and encourage patients
to adhere to therapy. This model was
developed for chronic malignant pain. At
each step, other modalities (eg, psychological
therapy and rehabilitative therapies)
can help improve function and
ensure that patients accrue maximum
benefit from analgesics.
In the past, pain experts could not
agree on a model addressing chronic
nonmalignant pain. Today, a few controlled
studies and many uncontrolled
studies validate opioid use in chronic
nonmalignant pain.1-7 Opioids provide
effective analgesia with acceptable side
effects in a wide range of chronic nonmalignant
pain conditions.8,9 Many
clinicians and patients still avoid
opioids, however, as myths and
misconceptions about the medicines
persist. They often have concerns
about addiction, intolerable
and potentially dangerous side
effects, and functional deterioration.10,11 Regulatory scrutiny also is
a concern for clinicians.11
The treatment goal for chronic
nonmalignant pain is to relieve
the pain and improve function.7
Complete pain relief may not be
achievable or realistic (and this
is a key point that patients and
clinicians must understand), but
improved functioning usually is.
Prescribers who treat patients with
chronic pain usually develop specific
goals for functional improvement
with individual patients.12,13 These
may be as simple as, "The patient will
be able to garden for 1 hour by the end
of the week," and pharmacists can ask
patients if they understand what their
specific functional goals are.
When the patient takes aspirin, acetaminophen,
or NSAIDs regularly, counseling
should begin with inquiring about
the dose and dosing schedule if the analgesic
is OTC. In addition, ask the patient
about aspirin allergies and allergies to
other pain relievers. Scan the patient's
profile for anticoagulants, and ask about
any history of gastrointestinal (GI) bleeding
or ulcers. Patients who have liver disease,
or those who consume 3 or more
alcoholic beverages a day, should avoid
acetaminophen. It is prudent to remind
patients that many OTC and prescription
pain medicines contain acetaminophen;
they need to read labels carefully, so they
do not approach or exceed the maximum
daily dose (4 g/day for adults; 2.4 g/day for
seniors and people with hepatic impairment).
Many NSAIDs are available in both
OTC and prescription forms, which often
confuses patients. If they receive a prescription-strength NSAID, explain that it
is stronger than the OTC version, and
also tell them what brand and generic
names are the same medication. The
FDA has revised labeling for all prescription
NSAIDs to include a boxed warning
stressing the potential for increased
risk of adverse cardiovascular events.14
In addition, patients also need to be
aware that the risk of GI bleeding is well
established, and they should know what
signs to watch for. Dose reductions may
be necessary if they have renal impairment.
Should patients need to step up to
opioid relief, pharmacists will need to
ask them about their beliefs and concerns. Patients who fear addiction (an
unpredictable, compulsive, psychological
craving for euphoria that appears in 10%
to 20% of the population) will need to
understand its difference from abuse and
dependence. Adhering to medications
as prescribed prevents abuse. Physical
dependence is predictable, and patients
usually develop some degree of physical
dependence after receiving opioids regularly
for more than 5 to 7 days. Patients
who take opioids chronically for pain will
experience withdrawal if they stop them
abruptly, reduce their dose too quickly, or
receive an opioid antagonist. If treatment
must be discontinued, using a tapering
regimen helps to avoid withdrawal.15
Sometimes, explaining that a similar
phenomenon can occur with the chronic
use of many classes of medications—
including nitro vasodilator therapy,
α2-adrenergic agents, corticosteroids,
and antidepressants—helps take away
some of the trepidation.16 Avoid using
stigmatizing terms, such as "addiction"
and "detoxification," to describe patients
who are physically dependent on opioids.
16 Opioid use for pain management
is seldom associated with the development
of addiction, unless a patient has a
predisposition to substance abuse prior
to opioid therapy.1,15,17 Pseudoaddiction
is a term used to describe behavior that
may occur when pain is undertreated,
but this condition is beyond the scope of
Tolerance to opioids' desired (analgesic)
and undesired (adverse) effects will
develop, but rates vary among patients.19,20
Tolerance predictably creates the need for
more frequent doses, or increasing doses,
to achieve the same effect.21,22 Tolerance
does not indicate addiction.23 This differential
rate of development explains the safe
use of large doses of opioids in patients
without causing respiratory depression.20,22
If tolerance to analgesia develops, it often
To delay the development of tolerance,
clinicians often combine opioids with
nonopioids or adjunctive therapy, which
Side effects cause nonadherence more
often than tolerance to analgesia does.
Counseling patients that certain side
effects will lessen with time is imperative
Chronic pain can be treated successfully
as long as the patient and all members
of the health care team recognize that a
goal of a completely pain-free existence
may be unreasonable. Additionally, if
treatment includes opioids, every member
of the team needs to stress proper
adherence, meaning that neither overadherence
nor underadherence is acceptable.
Sadly, it also means paying careful
attention to record keeping, in the event
that the regulatory agency has questions.
Perhaps some day, we will have drugs
that provide pain relief without the shadow
of abuse and addiction complicating
Tolerance to Opioid Side Effects
Cognitive: sedation, confusion, mood changes and sensory changes (eg, visual and auditory illusion, hallucinations, and delirium)
• Cognitive effects usually occur during the first 2 weeks of
therapy or following a dose increase, although tolerance
to these effects usually develops rapidly
• Opioid-dependent patients (ie, those stabilized on longterm
opioid therapy) may retain driving skills
• The greatest potential impairment occurs during the first
few days of use and during the first few hours after a
Nausea and vomiting
• In most patients, tolerance develops during the first
week of therapy
• Prophylactic antiemetics may be needed in patients with
a history of motion sickness or severe opioid-induced
Constipation: a reduction in bowel movement frequency
to less than 1 every 3 days, or difficulty passing stool
• Tolerance to the GI effects of opioids develops very
slowly, if at all. Constipation is likely to persist in most
• Prophylactic use of stimulating cathartic drugs (eg, bisacodyl,
senna), with the addition of stool softeners, particularly
in the elderly or in patients with coexisting GI
pathology, is crucial
• Encourage increased fluid and dietary fiber intake
• Rare when the opioid dose is carefully titrated to the
• If clinically significant respiratory depression occurs,
administer opioid antagonists, titrated carefully to prevent
opioid withdrawal symptoms
GI = gastrointestinal.
Adapted from references 5, 15, 19, and 23-36.
- Aronoff GM. Opioids in chronic pain management: is there a significant risk of addiction? Curr Rev Pain. 2000;4:112-121.
- Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Menskey H . Randomised trial of oral morphine for chronic non-cancer pain. Lancet. 1996;347:143-147.
- Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine. 1998;23:2591-2600.
- Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003;348:1223-1232.
- Allan L, Hays H, Jensen NH, et al. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001;322:1154-1158.
- Ytterberg SR, Mahowald ML, Woods SR. Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum. 1998;41:1603-1612.
- Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60:927-934.
- Portenoy R. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage. 1996;11:203-217.
- Bartleson JD. Evidence for and against the use of opioid analgesics for chronic nonmalignant low back pain: a review. Pain Med. 2002;3:260-271.
- Roth SH. A new role for opioids in the treatment of arthritis. Drugs. 2002;62:255-263.
- Nedeljkowic SS, Wasan A, Jamison RN. Assessment of efficacy of long-term opioid therapy in pain patients with substance abuse potential. Clin J Pain. 2002;18(4 Suppl):S39-S51.
- Kalso E, Allan L, Dellemijn PLI, et al. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain. 2003;7:381-386.
- Marcus DA. Tips for managing chronic pain. Implementing the latest guidelines. Postgrad Med. 2003;113:49-50, 55-56, 59-60 passim.
- An analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf. Accessed February 17, 2008.
- Cherny NI. Opioid analgesics: comparative features and prescribing guidelines. Drugs. 1996;51:713-737.
- American Pain Society. Liaison Committee on Pain and Addiction. Definitions Relating to the Use of Opioids for the Treatment of Pain. www.ampainsoc.org/advocacy/opioids2.htm. Accessed February 17, 2008.
- Savage SR. Opioid therapy of chronic pain: assessment of consequences. Acta Anaesthesiol Scand. 1999;43:909-917.
- Weissman DF, Haddox JD. Opioid pseudoaddiction--an iatrogenic syndrome. Pain. 1989;36:363-366.
- Nicholson B. Responsible prescribing of opioids for the management of chronic pain. Drugs. 2003;63:17-32.
- Anderson S, Leikersfeldt G. Management of chronic non-malignant pain. Br J Clin Pract. 1996;50:324-330.
- American Society of Addiction Medicine. Public policy statement on definitions related to the use of opioids in pain treatment. J Addict Dir. 1998;17:129-133.
- Foley KM. Misconceptions and controversies regarding the use of opioids in cancer pain. Anticancer Drugs. 1995;6(Suppl 3):4-13.
- Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18(4 Suppl):S3-S13.
- O'Mahony S, Coyle N, Payne R. Current management of opioid-related side effects. Oncology (Williston Park). 2001;15:61-73, 77; discussion 77-78, 80-82.
- Fishbain DA, Cutler B, Rosomoff HL, Rosomoff RS. Are opioid-dependent/tolerant patients impaired in driving-related skills? A structured evidence-based review. J Pain Symptom Manage. 2003;25:559-577.
- Zacny JP. A review of the effects of opioids on psychomotor and cognitive functioning in humans. Exp Clin Psychopharmacol. 1995;3:432-466.
- O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnas K. The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain. 2000;85:209-215.
- Sjogren P, Olsen AK, Thomsen AB. Neuropsychological performance in cancer patients: the role of oral opioids, pain and performance status. Pain. 2000;86:237-245.
- Banning A, Sjogren P, Kaiser F. Reaction time in cancer patients receiving peripherally acting analgesics alone or in combination with opioids. Acta Anaesthesiol Scand. 1992;36:480-482.
- Vainio A, Ollila J, Matikainen E, Rosenberg P, Kalso E. Driving ability in cancer patients receiving long-term morphine analgesia. Lancet. 1999;346:667-670.
- Bruera E, Macmillan K, Hanson J, MacDonald RN. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain. 1989;39:13-16.
- Sjogren P, Thomsen AB, Olsen AK. Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy. J Pain Symptom Manage. 2000;19:100-108.
- Byas-Smith MG, Chapman SL, Reed B, Cotsonis G. The effect of opioids on driving and psychomotor performance in patients with chronic pain. Clin J Pain. 2005;21:345-352.
- Galski T, Williams JB, Ehle HT. Effects of opioids on driving ability. J Pain Symptom Manage. 2000;19:200-208.
- Sabatowski R, Schwalen S, Rettig K, Herberg KW, Kasper SM, Radbruch, L. Driving ability under long-term treatment with transdermal fentanyl. J Pain Symptom Manage. 2003;25:38-47.
- Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage. 2002;24:71-90.