Dependence on opioid pain medication: a framework for diagnosis and treatment

Jane C Ballantyne, University of Washington, Seattle

What is addiction?

Mrs S is a 65 yr old with failed back syndrome on high dose fentanyl patch. She presents to the Pain Clinic in much distress. Her husband is with her and is also distressed. She is leaning over the exam table throughout the consultation, and grimacing throughout. She can hardly speak she is in so much pain, so her husband fills in.

We decide to convert her to methadone on the basis that she may have developed tolerance to fentanyl. Initially she does well on methadone, pain is greatly improved and they are both happier.

She returns to the Clinic (early), again in great pain distress. The story is that she has been vomiting up the methadone and is not getting any pain relief. She has run out of methadone 2 weeks early. Her husband is in tears stating it is all his fault because he gave her too much, and he can’t bear to see her suffering. After controlling her pain with IV ketorolac, we discuss options (at length) and eventually agree to try methadone suppositories. The clinic pharmacist arranges for a compounding pharmacy near their home to make up the suppositories. However, they leave in a hurry stating that they need help immediately and will go to the emergency room.

Kreek, LaForge & Butelman Nat Rev Drug Discov 2001;1:710-26

Substance abuse Maladaptive drug seeking that does not meet criteria for “substance dependence”, in part because of lack of tolerance and physical dependence

Substance dependence (“drug addiction”)Maladaptive drug seeking together with tolerance and dependence

Concept of layers of substance use disorder now abandoned

Use of the word “dependence” to mean addiction now abandoned

DSM III and IV

1.Historic notes

2.Neurobiology

3.DSM V

4.Dependence vs. addiction

Historic notes

Before 1950s

• Addiction considered a weakness of character or control, not a medical illness

• Understanding of addiction neurobiology was rudimentary

• Existence of endogenous opioid system only imagined

1950s

• First DSM (1952) grouped alcohol and substance abuse under Sociopathic Personality Disturbances

• Did not recognize the key role of tolerance and withdrawal in drug addiction

• “Reward” center in the brain first recognized

• Addiction began to be understood as essentially a compulsive and pathological pursuance of natural “rewards”

1970s

• Discovery of opioid receptors, although addiction researchers had surmised the existence of the receptor types (μ, κ, δ and σ) earlier, and on the basis of pharmacological studies

• Discovery of endogenous opioids

Pert and Snyder Science 1973;179:1011-4Hughes et al Nature 1975;258:577-80

1980s

• DSM-III tolerance and withdrawal included as addiction criteria together with social and cultural factors

• Term “dependence” first used to denote drug addiction

• “Dependence” is distinguished from “abuse” which is considered a precursor to dependence or addiction

Neurobiology

The brain on opioidsThe brain that is exposed to opioids is different from the brain that is not exposed.

Nestler Neuron 1996;16:897Nestler Neuropharmac 2004:47 Suppl 1:24Cami & Farre NEJM 2003;349:975

Positive reinforcing effects

• mesocorticolimbic dopamine systems

• “reward circuits”

• cause euphoria and reinforcement of drug-seeking behaviors

Negative reinforcing effects

• withdrawal anhedonia (same system) during early withdrawal

• physical effects of withdrawal arising from physical dependence (upregulation of cAMP in locus ceruleus and other locations)

NOTE: Both are significant driving force in drug-seeking behavior, but must be distinguished from long-term drug craving which persists long after recovery from withdrawal

Stress and contextual clues

• Conditioning, powerful memory input

• Not easy to eradicate, even after drug cessation

• More incessant stimulation less easy to eradicate

• Structures involved are those involved in memory, conditioning and learning: amygdala, hippocampus, prefrontal cortex and thalamus

Enduring adaptations

• Explain relapse

• Result of complex interactions between drugs themselves and the circumstances under which they are taken

• Neuroadaptation occurs through gene regulation, remodeling of circuits, changes in intrinsic excitability, increased in synaptic strength, actual morphological changes

• These adaptations may also alter analgesia and tolerance

Cami, J. et al. N Engl J Med 2003;349:975-986

Metabotropic Mechanisms of Action of Drugs of Abuse

DSM V

What’s new about DSM V?

• No longer using the word “dependence”

• Abandoned the concept of a progression from abuse to dependence

• Because tolerance and dependence do not count as criteria for drug addiction when an addictive drug is being used medically, two (instead of one) behavioral criteria are needed

• It will therefore be more difficult to make a diagnosis of addiction in a patient receiving medical treatment

Ballantyne & LaForge Pain 2007;129:235-55

Dependence versus addiction

GRAY ZONE

ADDICTED NOT ADDICTED

Meets DSM criteria for addiction

• No lost prescriptions• No ER visits• No early prescriptions• No requests for dose

escalation• No UDT aberrancies• No doctor shopping

(PMP)

DSM V Behavioral criteria for Substance Use Disorder

A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by 2 or more of the following: • Failure to fulfill major role obligations at work, school or home• Continue in situations in which it is physically hazardous (eg driving)• Persistent or recurrent social or interpersonal problems • Substance taken in larger amounts or longer than was intended • Persistent desire or unsuccessful efforts to cut down• Great deal of time spent in activities necessary to obtain substance, use substance or

recover from substance use • Important social, occupations or recreational activities given up or reduced • Continued use despite knowledge of harm• Craving

Physical – regions of control of somatic function - locus ceruleus (noradrenergic nucleus)

upregulation of cAMP arousal, agitation, diarrhea, rhinorrhea, piloerection

Emotional/psychological – reward centers

hedonia anhedonia

Pain pathways

analgesia hyperalgesia

Ballantyne & LaForge, Pain 2007;129:235Ballantyne et al, Arch Int Med 2012;172:1342

Dependence is inevitable with continuous use

Drivers of opioid seeking:

Memory, including memory of pain, pain relief and euphoria

Pain, including withdrawal hyperalgesia, which may be subtle

Withdrawal anhedonia

Physical symptoms of withdrawal which may be subtle

Addiction (craving, compulsive use)

Koob et al, Trends Neurosci 1992;15:186Nestler & Aghajanian, Science 1997;278:58Hyman et al, Ann Rev Neurosci 2006;29:565

Dependence drives opioid seeking but is not necessarily addiction

• Tolerance is the need to increase dose to achieve the same effect

• Tolerance may develop for both the euphoric and analgesic effects of opioids

• Tolerance can be produced by both psychological (associative) and pharmacological (non-associative) factors

Ballantyne & LaForge Pain 2007;129:235

TOLERANCE

DEPENDENCE

WITHDRAWAL SYMPTOMS

CRAVINGOPIOID SEEKING

NORMAL

EUPHORIA

ANALGESIA

DYSPHORIA

HYPERALGESIA

What we understand about opioid dependence

PAIN

PAIN RELIEF

WORSE PAIN

• Pain and mood are interdependent whether opioid treated or not

• Pain patients taking opioids continuously develop tolerance and dependence

• For them, psychosocial stressors not only increase pain, as in non-treated patients, but also increase tolerance

• Doses are increased to avoid withdrawal and worsening pain

• Ultimately leads to the patient for whom no dose is enough

Ballantyne et al Arch Int Med 2012;172:1342

Enduring adaptations produced by established behaviors

For the illicit drug user:

• Procurement behaviors

For the pain patient – much more complex:

• Continuous opioid therapy may prevent opioid seeking• Memory of pain, pain relief and possibly also euphoria• Even if the opioid seeking appears as seeking pain relief, it

becomes an adaptation that is difficult to reverse• It is hard to distinguish between drug seeking and relief

seeking

The dependent/addicted pain patient

Not generally recognized as addiction

• Periodic requests for dose escalation• Refusal to try other treatments, claim of allergies• High pain score despite opioid• Not working/on disability• Anger

Generally recognized as addiction

• Doctor shopping (PMP)• Aberrant UDT• Frequent lost prescriptions

Summary points

• Patients who stay on opioid pain treatment long-term and continuously will inevitably develop dependence

• Dependence is not simply physical, nor is it easily reversed

• Distinguishing dependence from addiction is not easy in the setting of pain treatment with opioids

• Addiction is still not fully understood

• Since the treatment is similar, it may be better to avoid labels, or create a new label for dependency on prescription analgesics