Mrs S* is in her 80s and over the years has become progressively more immobilised from rheumatoid arthritis, compounded by osteoporosis. She is in chronic pain which has recently intensified as a result of compacted vertebrae.

The drugs of choice for the management of moderate to severe

Over the Last two decades there has been a Large amount of published research on the evaluation and treatment of pain and on barriers to effective pain management for those with terminal illness (2) and those with chronic non-malignant pain, such as Mrs S. (3,4) Barriers identified included erroneous beliefs and concerns of patients and their caregivers, as well as their health care providers. For health care professionals, key barriers identified were: attitudes and misconceptions about medications and their side effects, insufficient knowledge/ training in pain management and tack of format assessment procedures for pain. For patients and their caregivers, fear of addiction was the main barrier. Other barriers were anxiety about side effects, a perception that pain was inevitable and not wanting to complain. This was particularly found in older patients, those with Lower incomes or Less education and also in patients whose pain was not welt controlled. (2,4)

An important outcome of this research has been interventions and education programmes aimed at improving cancer pain management over the Last two decades and oncology nurses were reported to have more extensive knowledge in pain assessment and opioid addiction prevalence generally than non-cancer nurses. (5)

Early surveys of addicts published in the 1950s suggested a substantial risk of iatrogenic addiction from opioid therapy for pain. These observations, together with theoretical writings that Linked addiction to the pharmacological properties of tolerance and physical dependence, led to the perception that any exposure to opioid drugs would cause addiction in previously normal patients. However, surveys of cancer patients provided different data, and resulted in a changed attitude, leading to vastly improved pain management for cancer patients. (3,4)

A recent more contentious debate has been over the long-term use of opioids in the management of chronic, non-malignant pain. (6) Key concerns are tolerance and tong-term efficacy, persistent side-effects, compromised physical and psychosocial functioning and the risk of addiction. (3,7,9) A recent review reported that the prevalence of addiction varied from zero to 7.7 percent in cancer patients and from zero to 50 percent in chronic, non-malignant pain patients, varying with the subpopulation studied and the criteria used for addiction. (6)

The potential for physical dependence and iatrogenic addiction are clearly important factors to consider with respect to tong-term use of opioid drugs in the management of chronic, non-malignant pain and it is an important area of current research.

Significant factors that need to be considered when interpreting the research Literature include definitions of addiction, confusing nomenclature, selected patient groups and clinicians working in quite different specialist areas: the psychiatrist dealing with an increasing public health problem of drug addiction and the clinician dealing with the body and realities of chronic pain. These different paradigms are reflected in the published literature, in the addiction criteria used and in their interpretation.

How directly transferable is research relating to alcohol addiction and substance abuse to the use of narcotic analgesia for pain management? The fact that tolerance and withdrawal are Listed as the first two criteria in the American Psychiatric Association's DSM-IV criteria for substance dependence (see Table 1), a commonly used diagnostic tool, has contributed to a general perception that physical dependency implies addiction. An important source of confusion is the use of the term "dependent" or the inaccurate Label of addicted, and the stigma of thus describing patients who are physically dependent.

An understanding of the bioscience helps to clarify the very significant differences between these terms. Physical dependence develops as a result of ongoing exposure to a drug varying with dose, time, drug and potency. It is a physiological adaptation to the persistent presence of the drug. If the drug is withdrawn, especially if this occurs suddenly, the body needs to readjust physiologically and in the interim withdrawal symptoms develop. (7,10) These are, to some extent, predictable as they are generally the opposite of the drug's effects. Thus the symptoms of narcotic withdrawal include dysphoria (opposite of euphoria), anxiety, hyperactivity, goose-bumps, muscle spasms (opposite of depressant effect) and diarrhoea (opposite of constipation).

Rebound effects

Note that physical dependence also occurs with other drugs that have no addiction potential, such as beta-blockers, alpha-2-adrenergic agents (eg clonidine), some anticonvulsants and tricyclic antidepressants. With these drugs the symptoms that develop with withdrawal after extended use are generally referred to as "rebound effects" In physiological terms they are the equivalent of withdrawal effects--the need for the body to readjust physiologically to the fact the drug is no longer present.

Withdrawal symptoms, or rebound effects, are more pronounced with a sudden stop (going "cold turkey") and after a prolonged period of drug use. Symptoms are less marked with gradual withdrawal where the body can readjust slowly. Gradual withdrawal is the recommended management procedure for any drug where there is a risk of marked withdrawal or rebound effects.

The important concept from this is that repeated drug use by someone who is addicted wilt result in physical dependency. Withdrawal symptoms are distressing, quickly relieved by taking more of the drug, and so may lead on to addiction. However, where narcotics have been used for pain relief and withdrawal symptoms managed, addiction need not be an issue. (10) There is an important difference between addicts, who, in the absence of pain, self-administer a drug for a euphoric effect, and patients whose drug use is driven by their need for relief from pain.

Bioscience also helps to clarify the relationship between tolerance and addiction. One reason for drug tolerance--the need for an increasing dose to achieve the same physiological effect--is because with some drugs, repeated exposure may trigger increased production of specific microsomal CYP enzymes. These enzymes, found particularly in the liver, act to break down or inactivate the drug. Elevated Levels of these enzymes cause more rapid drug removal and therefore more drug is needed to achieve the same effect. Drugs that cause this increased CYP enzyme production are termed "inducers" and include potentially addictive drugs such as alcohol, benzodiazepines and barbiturates but also non-addictive ones such as Rifampicin, Griseofulvin, Carbamazepine, Vitamin C and Vitamin E. (11) Different levels of these CYP enzymes are not just linked with addiction--they may also cause drug-to-drug interactions and account for individual differences in drug responses.

At another physiological level, tolerance may arise due to "blunting" of the drug receptors. The basis of action for any drug effect is that they bind to specific receptor sites in the body, such as neurotransmitter receptors in the brain. A reduction in the number or sensitivity of these receptors means the body becomes "hard of hearing" with respect to the drug and more is required--much like too much Loud noise can cause someone to become hard of hearing, causing the need to shout to get the message through. This blunting of drug receptors' response, particularly in the "reward" centres of the brain, has been identified as an important and common feature of addiction to many substances, but may again also occur with non-addictive drugs such as Levodopa.

Dopamine-reward system

Addiction is complex, involving functional as welt as structural changes in the brain. It is a fascinating area of neuroscience research that is helping us understand why some are more vulnerable than others and that complex social-biological interactions involving genetic, pre-natal, social and environmental factors are involved. Addictive drugs are those that link up with certain neural circuits known as the dopamine-reward system in the limbic system, a part of the brain involved with emotions. An important function of this ancient reward pathway is that a surge of dopamine here causes the pleasure associated with eating and sex, and so has ensured survival of the species. It is the ability of addictive drugs to greatly amplify levels of dopamine in this reward centre, either directly or indirectly, that underpins the destructive craving that marks addictive behaviours, where an individual may sacrifice everything that is important to them--family, friends and their health--in their compulsive craving for the ultimate dopamine high.

But this brain reward system is functionally modulated by other neural systems, such as those that control impulsivity and the stress response. One hypothesis based on experimental data in animals and humans is that alterations in the hypothalamus-pituitary-adrenal (HPA) axis not only occur with, but may actually precede, addiction and so contribute to the vulnerability, persistence and relapse that make some at increased risk. (12) Individuals who have no predisposition to developing addiction may use narcotic analgesic drugs that stimulate the reward centre without the consequent development of addiction. (6,12,17)

Arising from insights gained from these diverse areas of research, different criteria for addiction have been developed that are more appropriate when opioids are used for pain relief (see Tables 2 and 3).

So the risk of addiction is an important consideration when initiating tong-term opioid treatment, especially in those who are at increased risk of this. But what about someone like Mrs S? Surely here the important factors are effective pain control and narcotic-related adverse effects such as constipation, nausea, possible mental clouding, sedation and respiratory depression, especially where breathing is already compromised. Individual differences in analgesia response and efficacy of different drugs and strategies for pain relief are also important factors. (18,20) Concerns about adverse effects aLso apply with long-term use of other analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant drugs such as antidepressants, particularly in the elderly. (21) Narcotic drugs are powerful analgesics and the possibility of addiction and abuse may present as a problem (9) but concerns about addiction may also impede effective pain management and quality of life. It is important that physical dependence, with its related problem of withdrawal, is clearly distinguished from addiction, which is more accurately defined as a "compulsive use of a substance resulting in physical, psychological or social harm to the user and continued use despite that harm. " Guidelines have been developed to identify those at increased risk. (3,6,8)

Recent research also cautions that a request for increasing a dose may be misinterpreted as drug-seeking behaviour, but instead may be due to increasing pain as a result of disease progression or the development of physiological tolerance. (6) Also, one consequence of narcotic withdrawal, unless this is appropriately dealt with, is increased sensitivity to pain.

Assessing the balance between beneficial effects and potential adverse effects applies to any intervention, including the use of opioids for pain relief. Of relevance to Mrs S is that some recent studies found the risk of developing tolerance and the resulting reduced efficacy of opioid analgesics was reported to be less for older patients who, conversely, may be at risk of gastric ulcers and cardiac and kidney damage linked with the use of NSAIDs. (22,23)

Increasing understanding of pain

Over the last 30 years in particular, effective pain management has developed as an important multi-discipline speciality that aims to provide the best possible quality of Life for those dealing with chronic pain. (1,19,24) This has paralleled our increasing understanding of pain. Pain has different aspects--cognitive, affective and behavioural--and pain threshold and pain tolerance varies, between individuals and in different circumstances. (20) Attitudes towards pain have changed. In the 19th century there was debate regarding the use of anaesthesia gases with surgery and childbirth based on morality, with the belief that God inflicted pain to strengthen faith and to teach self-sacrifice. In the 20th century there was an attitude that "every effort should be made to put off [narcotic use] until all other measures have been exhausted" and the patient's Life "can be measured in weeks" (24) because physical dependency was perceived as addiction with all its stigma.

A recent research review concludes that "if opioid treatment results in pain control, better, functioning and improved health-related quality of life, the treatment should of course be continued, even in patients susceptible to addiction. But these patients will need special attention with focus on compliance and with an open-minded dialogue about the potential problems and the consequences if the opioid treatment is getting out of control". (6)

This concurs with a consensus statement that supports the use of opioid analgesics while recognising their potential for abuse. Among its signatories are the American Medical Association, American Society of

Addiction Medicine, American Academy of Pain Medicine and American Pain Society. (6,25)

One could add to that an awareness of the important distinction between physical dependency and addiction: the addict who self-administers a drug in the absence of pain, and the person whose drug use is driven by the desire for pain relief; as well to what extent attitudes and our Limited knowledge have affected past practice. Physical dependency is not moral failure.

References

(1) World Health Organisation. (1990) Cancer pain relief and palliative core (804). Geneva: WHO Technical Report.

(2) Pargeon, K.L. & Hailey, B.J. (1999) Barriers to effective cancer pain management: a review of the Literature. Journal of Pain and Symptom Management; 18: 5, 358-68.

(3) Portenoy, R.K. (1996) Opioid therapy for chronic nonmalignant pain: a review of the critical issues. Journal of Pain and Symptom Management; 11: 4, 203-217.

(4) Auret, K. & Schug, S. (2006) Underutilisation of opioids in elderly patients with chronic pain--approaches to correcting the problem: a review. Drugs & Aging; 22: 8, 641-654.

(5) Glajchen, M. & Bookbinder, M. (2001) Knowledge and perceived competence of home care nurses in pain management: a national, survey. Journal of Pain and Symptom Management; 21: 4, 307-316.

(6) Hojsted, J. & Sjogren, P. (2006) Addiction to opioids in chronic pain patients: a literature review. European Journal of Pain; 11, 490-518.

(7) Molea, J. & Augustyniak, M. (2006) Chronic pain management: Is addiction a risk? Is consultation a necessity? Techniques in Regional Anesthesia and Pain Management; 9, 187-194.

(8) Naliboff, B., Wu, S. & Pham, Q. (2006) Clinical considerations in the treatment of chronic pain with opiates. Journal of Clinical Psychology: In Session; 62: 11, 1397-1408.

(9) Tedeschi, M. (2006) Chronic nonmalignant pain: the rational, use of opiod medication. Australian Family Physician; 35: 7, 509-512.

(10) Seddon, S.R. (2002) Assessment for addiction in pain-treatment settings. Clinical Journal of Pain; 18: 4, $28-$38.

(11) Calvey, N. (2006) Enzyme inducers and inhibitors: addition, subtraction and synergism. Anaesthesia and Intensive Care Medicine; 6: 4, 139-140.

(12) Kreek, M.J., Schlussma, S.D., Bart, G., LaForge, K.S. & Butelman, E.R. (2004) Evolving perspectives on neurobiological, research on the addictions: celebration of the 30th anniversary of NIDA. Neuropharmacology; 47, 324- 344.

(13) Heinz, A. (2006) Staying sober: better understanding of how alcohol alters brain chemistry reveals mechanisms for beating dependency. Scientific American Mind; April/May, 57-61.

(14) deLecea, L., Jones, B.E., Boutrel, B., Borgland, S.L., Nishino, S., Bubser, M. & DiLeone, R. (2006) Addiction and arousal: alternative roles of hypothalamic peptides. Journal of Neuroscience; 26:41, 10372-5.

(15) Nestler, E. J. & Malenka, R.C. (2004) The addicted brain. Scientific American; March, 50.

(16) DeVries, T.J. & Shippenberg, T.S. (2002) Neural systems underlying opiate addiction. Neural Systems Underling Opiate Addiction; 22: 9, 3321-5.

(17) Savage, S.R. (2002) Assessment for addiction in pain-treatment settings. Clinical Journal of Pain; 1-8: 4, S28- S38.

(18) Inturrisi, C.E. (2002) Clinical. pharmacology of opioids for pain. Clinical Journal of Pain; 18: 4, S3-13.

(19) McCaffery, M. & Pasero, C. (1999) Pain Clinical Manual St. Louis: Mosby.

(20) Holdcroft, A. & Power, I. (2003) Recent developments: management of pain. British Medical Journal; 326, 635-9.

21) Ferrell, B.A. (2002) The management of pain in long-term care. Clinical Journal of Pain; 20: 4, 240-3.

(22) Spurgeon, D. (2005) Older patients are at smaller risk of opioid tolerance than younger patients. British Medical Journal; 330, 1230.

(23) Buntin-Mushock, C., Phillip, L., Moriyama, K. & Palmer, P.P. (2005) Age-dependent opioid escalation in chronic pain patients. Anesthesia and Analgesia; 100: 6, 1740-5.

(24) Meldrum, M.L. (2003) A capsule history of pain management. Journal of the American Medical Association; 290: 18, 2470-5.

(25) American Academy of Pain Management and the American Pain Society. (1997) The use of opioids for the treatment of chronic pain: consensus statement. Clinical Journal of Pain; 13: 1, 608.

Suzi Penny, BSc, MSc, is a Lecturer in Life Sciences at the Institute of Food Nutrition and Human Health at Massey University. Penny watched her own father die from cancer in pain 30 years ago. Mrs S* is a case study known to the writer.

TABLE 1 (6)

DSM-IV Diagnostic criteria for substance dependence A maladaptive
use, leading to clinically significant impairment or distress, as
manifested by three or more ol the following, occurring at any time
in the same 12-months period:

1) Tolerance, as defined by either the following:

a. A need for markedly increased amounts of the substance to
achieve intoxication or a desired effect

b. Markedly diminished effect with continued use of the same amount
of the substance

2) Withdrawal, as manifested by either of the following:

a. The characteristic withdrawal symptom for the substance

b. The same (or closely related) substance is taken to relieve or
avoid withdrawal symptoms

3) The substance is often taken in larger amounts over a longer
period than was intended

4) There is a persistent desire or unsuccessful efforts to cut down
or control substance use

5) A great dear of time is spent in activities despite knowledge of
having a persistent physical, or psychological, problem that is
likely to have beren caused or exacerbated by the substance (eg.
current cocaine use despite recognition of cocaine induced
depression or continued drinking despite recognition that an ulcer
was made worse by alcohol, consumption)

The symptoms for substance abuse are:

1) Recurrent substance use resulting in failures to fulfil major
role obligations at work, school or home

2) Recurrent substance use in physically hazardous situations (eg
driving or operating a machine when impaired by substance use

3) Recurrent substance related legal, problems. Continued substance
use despite persistent or recurrent social, or inter-personal
problems caused by the effects of the substance

TABLE 2 (6)

According to the international classification
of Diseases (ICD-10), WHO 2003, a definite
diagnosis requires that three or more of six of
the following characteristic features have been
experienced or are exhibited:

* a strong desire to take the drug

* difficulties in controlling its use

* persisting in its use despite harmful consequences

* a higher priority given to the drug use than to
other activities and obligations

* increased tolerance and sometimes a physical
withdrawal state.

TABLE 3 (6)
Aberrant drug related behaviours that raise concern about the
potential for addiction in medical patients prescribed opioids
for chronic pain

Probably more predictive of addiction

Selling prescription drugs
Prescription forgery
Stealing or "borrowing" drugs from others
Injecting oral formulations
Obtaining prescription drugs from non-medical, sources
Concurrent abuse of alcohol or illicit drugs
Multiple dose escalation of other non-compliance with therapy despite
warnings
Multiple episodes of prescription "Loss"
Repeatedly seeking prescription from other clinicians or from emergency
rooms without informing prescriber or after warning to desist
Evidence of deterioration in the ability to function at work, in
the family, or socially that appear to be related to the drug use
Repeated resistance to changes in therapy despite dear evidence of
adverse physical or psychological effects from the drug,

Probably less predictive of addiction
Aggressive complaining about the need for more drug
Drug hoarding during periods of reduced symptoms
Requesting specific drugs
Openly acquiring similar drugs from other medical sources
Unsanctioned dose escalation or other non-compliance with therapy on
one or two occasions
Unapproved use of the drug to treat another symptom
Reporting psychic effects not intended by the clinician
Resistance to change in therapy associated with "tolerable" adverse
effects with expressions of anxiety related to the return of severe
symptoms.