One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substances for non-legitimate purposes.[1][2]

A common reason people seek the care of medical professionals is pain relief. While many categories of pain medications are available, opioid analgesics are FDA-approved for moderate to severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. The prescribing of opioid analgesics for chronic pain is controversial and fraught with inconclusive standards.

In the 1990s, due to the chronic failure of health professionals to undertreat severe pain, opioid analgesic prescribing was expanded. Unfortunately, this led to increased overuse, diversion of drugs, opioid use disorder, and overdose. The "Catch-22" seems to be either health professionals undertreat, and there is needless suffering, or they overtreat, with a potential to cause adverse effects like increased opioid analgesic use disorder and potential overdose.

The prescription of opioid analgesics peaked in 2011, since then both prescribing and overdose has been declining; yet as a society, in both the lay and scientific literature, there are grave concerns that we are still in the middle of an opioid crisis.[3]

Perhaps the biggest challenge of caring for patients with pain is that individuals have different levels of tolerance and require variable opioid doses to obtain adequate pain relief. Patients may have a range of behavioral, cultural, emotional, and psychologic responses to pain versus a substance use disorder; often it is challenging to tell the difference. All health professionals engaged in pain management need an understanding of the treatment recommendations and safety concerns in prescribing opioid analgesics. Appropriate opioid prescribing requires a thorough patient assessment, short and long-term treatment planning, close follow-up, and continued monitoring. All providers need to be aware of not only appropriate patient assessment and treatment planning but also the possibility of use disorder, diversion, and potentially dangerous behavioral responses to controlled substances, e.g., opioid analgesics differ from pseudo-addiction and physical dependence.

It is unfortunately clear that many clinicians know little about opioid use disorder; they do not understand it is a disease, and many believe opioid dependence is the same as opioid use disorder. Lack of a clear understanding results in clinicians confusing a chronic non-use disorder pain patient from the one who is misusing their prescribed opioid. Lack of training and educational deficits often interferes with the appropriate prescription of opioid analgesic agents. To prevent misuse of controlled substances, providers that prescribe controlled substances should learn prescribing practices that minimize or prevent adverse consequences.[4]

Definitions

• Addiction - according to the American Society of Addiction Medicine (ASAM) - "Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychologic, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward or relief by substance use and other behaviors." Addiction is now termed "use disorder," and is characterized by an inability to consistently abstain, craving, impairment in behavioral control, diminished ability to recognize significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, use disorder is progressive and can result in disability or premature death."[5] 

• Appropriate opioid prescribing - providing pain control while minimizing use disorder or risk of same, and toxicity; and implementing safeguards to reduce drug diversion.

• Inappropriate opioid analgesic prescribing - non-, inadequate, excessive, or continued prescribing despite evidence of the lack of effective opioid treatment.

• Controlled substances - drugs or medications that possess the potential for being misused and are considered to be substances that have a substantially high risk of resulting in substance use disorder.

• Narcotics - comes from the Greek word for stupor and originally referred to drugs that dulled the senses and relieved pain, e.g., morphine. Also, narcotics were any drug that induced sleep. A more precise term for this class of drugs, with less uncertainty regarding its meaning, is opioid analgesics. Please note that the Drug Enforcement Administration (DEA, USA) uses the term narcotic to refer to drugs that are opioid analgesics.

Five Characteristics of Addiction/Use Disorder (ASAM)

1. Craving for drug or reward
2. Diminished recognition of significant problems in one's behavior
3. Dysfunctional emotional response
4. Impairment in behavioral control
5. Inability to consistently abstain 

Drug Schedules of Controlled Substances

All providers should be familiar with the guidelines and laws for each schedule which have as their basis the purpose of the drug and the risk of use disorder. In the United States, controlled substances are under strict regulation by both federal and state laws which guide their manufacture and distribution. Controlled substances have a high risk of resulting in an addiction and substance use disorder. As the schedules decrease, I-V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder. 

Controlled Substance Act

In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970, and it included the Controlled Substance Act. The Controlled Substance Act covers drug:

• Classification and regulation, according to their content and purpose
• Manufacturing
• Distribution
• Exportation and sale

The Controlled Substance Act established five drug schedules and classified them to control their manufacture and distribution. Part of regulation requires providers that prescribe scheduled drugs and pharmacists that fill them to obtain a license from the Drug Enforcement Administration. Health professionals licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a particular provider or distributor.

Of the five schedules, each has parameters based on their medical value, the risk of addiction, and ability to cause harm. The schedules range from schedule I (most potential for addiction and use disorder) to schedule V (least potential for addiction/use disorder).

Schedule I

• Schedule I drugs possess the highest potential for use disorder and misuse. They have no medical use and are illicit or “street” drugs.
• Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine (MDMA), and methaqualone.
• Marijuana, which is legal in some states, is still classified as a Schedule I drug at the federal level as of this writing.

Schedule II

• Schedule II drugs have a reduced potential for use disorders than I. They are high risk for both physical and psychological dependence. They have a high capacity for both use disorder and misuse. They are typically prescribed to treat severe pain, anxiety, insomnia, and ADHD.
• Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, fentanyl, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital.
• They previously had to be prescribed only via paper prescription, but now are permitted to be electronically transmitted. (Electronic Prescribing of Controlled Substances or EPCS).
• No refills are allowed. 
• Schedule II drugs have the tightest regulations when compared to other prescription drugs.

Schedule III

• Schedule III drugs are those with a lower misuse potential than I and II. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, or anesthesia or appetite suppression.
• Examples of Schedule III substances include benzphetamine, ketamine, phendimetrazine, and anabolic steroids.
• Opioid analgesics in this schedule include products containing not more than 90 milligrams of codeine per dosage unit, and buprenorphine.
• Schedule III drugs are prescribable verbally over the phone, with a  paper prescription, or via EPCS.
• Within a six-month time frame, refill requirements are such that the drug can only have five refills. 

Schedule IV

• Schedule IV drugs have an even lower misuse potential than I, II, or III. They have a limited risk of physical or psychological dependence.
• Examples of Schedule IV substances include: alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol, and triazolam.
• Drugs in this class may be utilized for pain control as long as the provider deems the drug to be medically necessary and that the patient would benefit.
• Schedule IV drugs are prescribable verbally over the phone, with a  paper prescription, or via EPCS.
• Refills are permitted up to five times in a six-month timeframe from the issuance date.

Schedule V

• Schedule V drugs are the least likely controlled substances to be misused. They result in very limited physical dependence or psychological dependence.
• Examples include cough medicines with codeine, antidiarrheal medications that contain atropine/diphenoxylate, pregabalin, and ezogabine.
• Schedule V drugs despite their low abuse potential, still need to be managed appropriately and administered with care.
• When they contain codeine, it must have less than 200 mg of codeine per 100 mL.
• Partial prescription fills cannot occur more than six months after the date of issue. When a partial fill occurs, it is treated in the same manner and with the same rules as a refill of the drug.

Drug Use Disorder, Abuse, and Misuse

Use disorder of a drug differs from abuse and misuse of a drug.

The drugs taken may be illicit street or stolen drugs or obtained via a legal prescription. Misusing a drug usually involves taking the drug in a harmful or detrimental way that results in personal, professional, or social problems. A patient that is abusing an opioid analgesic may no longer be appropriately interacting with their family, friends, or be able to perform their duties at work.

Misuse of a controlled substance refers to the use of a prescribed drug in a way that was not intended. It may be deliberate or accidental. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose route, or using prescription drugs written for another person.

Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both have the potential to be abused or misused. While schedule I drug use is illegal, prescription drugs found in schedules II-V are also commonly abused and misused, and their misuse is a challenging problem that has increased over the last several years.

The Centers for Disease Control and Prevention has declared prescription drug abuse is a problem of epidemic proportions. The CDC believes that absent checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, the potential for abuse and misuse will continue to increase.

Pill Shopping

Unfortunately, a common practice among those that deliberately misuse controlled substances is to seek out multiple sources of drugs. They do this by seeing different health care providers, and they present with a different list of complaints that are often fictitious and different for each provider. The patient may be able to obtain multiple prescriptions and then fill them at different pharmacies. Many states have enacted systems that allow providers to see all of the prescriptions written for each patient. Use of these systems is gradually curbing "pill shopping."[6]

Diversion

Some prescription drugs will sell on the street for as much as $50 a tablet. Diversion is when a patient sells their drugs as a method of earning money. Drugs may also be sold to buy food, pay expenses, or purchase more potent street drugs. Worse, in some cases, healthcare providers may divert drugs from patients for the providers own personal use or sell them to someone else.

Some individuals use controlled substances in ways for which they were not originally intended. Rather than pain control, they may be used to stay awake, induce sleep, or get "high." Before the popularity of prescription drug diversion, the only method to obtain illicit drugs was to import from other countries or manufacture them in private labs. Today, law enforcement agencies have the tremendous challenge of dealing with prescription drugs sold by diversion as well as illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity as well as dangerous overdoses and death. 

Methods of Obtaining Prescription Drugs

A review of multiple studies demonstrates a variety of means individuals obtain prescription drugs. The following summarizes the studies' findings.

• 55% free from a friend or relative
• 20% from a prescriber
• 10% purchased from a friend or relative
• 5% stolen from a friend or relative
• 5% purchased from a drug dealer
• 2% from multiple doctors
• 1% from theft from medical practice or pharmacy
• Less 1% from internet

Studies also reveal the source of the majority of these drugs was a single legal prescriber.

The pain associated with acute injuries may require scheduled drug treatment.  For some patients, the acute pain experienced may become chronic. Pain can be the result of neurologic and musculoskeletal conditions. Pain may also be local or systemic as a complication of diseases.[7]  Chronic pain syndromes have associations with many long-term conditions and diseases.

COMMON CAUSES OF LEGITIMATE PAIN

Neurologic and Systemic Diseases that Cause Pain

• Alcoholism
• Ankylosing spondylitis
• Brachial plexus traction injury
• Cancer
• Complex Regional Pain Syndrome
• Diabetic polyneuropathy
• Drugs
• Fibromyalgia
• Giant Cell Arteritis
• Glaucoma
• Infections
• Migraine
• Osteoarthritis
• Osteomalacia
• Pernicious anemia
• Polymalgia rheumatica
• Polyneuropathies
• Polyradiculopathies
• Postherpetic neuralgia
• Rheumatoid arthritis
• Side effects of chemotherapy or radiation therapy
• Sjogren syndrome
• Spinal stenosis
• Systemic lupus erythematosus (SLE)
• Smoking
• Temporomandibular joint dysfunction
• Thoracic outlet syndrome
• Trigeminal neuralgia
• Thyroid disease

Psychological Causes of Pain

• Anxiety
• Depression
• Emotional disorders
• Personality disorders
• Sleep disorders

Musculoskeletal Causes of Pain

• Ankylosing spondylitis
• Chronic overuse
• Dislocations
• Fractures
• Muscular Strains
• Myofascial diseases
• Polymyalgia rheumatica
• Polymyositis
• Osteomyelitis
• Osteoarthritis
• Osteoporosis
• Rheumatoid arthritis
• Mechanical back injury

COMMON CAUSES OF SITUATIONS RESULTING IN ILLEGITIMATE USE OF CONTROLLED SUBSTANCES

Any of the above conditions and causes of acute pain may progress to chronic pain. When there is chronic use of pain medicine, the risk of developing use disorder to a controlled substance to control the pain increases. Risk factors for a use disorder to a pain medication include:

• Age
• Life circumstances
• Medical problems
• Physical problems

Factors that increase the risk of developing use disorder include:

• If an individual uses drugs to stay awake or sleep, they are at increased risk of developing use disorder
• If an individual undergoes exposure to other individuals with use disorder, they are at a higher risk of developing use disorder
• If a parent has use disorder, there is a greater chance the children will develop use disorder
• If an individual engages in prescriber shopping, they are at increased risk of use disorder
• If an individual receives multiple drugs from multiple prescribers, they are at a higher risk of addiction

Factors that decrease the risk of use disorder include:

• Middle-aged
• No psychiatric history
• Relaxed personality
• Those that follow instructions

Acute and chronic pain is a significant problem in the United States and worldwide. In the United States alone it affects more than 100 million Americans annually. The cost of evaluating and treating pain is substantial, estimated to be over 600 billion dollars per year, including those unable to work as a direct consequence of pain syndromes.

PAIN FREQUENCY

Pain is among the primary reasons individuals receive federal and private disability payment support.

• Pain syndromes affect as much as 50% of the United States population at some point in their lifetime.
• For those over 21 years of age, approximately 10% have experienced pain for 3-12 months, and almost 50% have had pain longer that one year. Nearly half report their pain is uncontrolled.
• Over 5 million Americans are receiving long-term opioid analgesics for chronic pain. For many of those, the pain is disabling.

The frequency of acute and chronic pain is believed to be increasing for several reasons:

• The increased average age of the population
• Increased diversion of pain medications due to state and federal enforcement of illicit drugs
• Increased frequency of surgery and post-operative pain management with opioid analgesics
• Increased obesity with comorbid problems such as muscle strain and joint deterioration
• Increased treatment of pain
• Increased survival of military and civilians with traumatic conditions has increased with increased numbers in pain during recovery

FREQUENCY OF OPIOID RELATED CONCERNS

The Frequency of Opioid Prescribing and Consumption

• Even though the lay literature reports that opioid prescribing is on the rise, actually opioid analgesic prescribing is declining.
• Hydrocodone, methadone, and fentanyl prescribing has decreased by as much as 1/3rd since peaking in 2011.
• Before 1990, physicians rarely prescribed opioids for noncancer pain. Starting in the 1990's physicians were encouraged to control pain as this was the "fifth vital sign." The use of opioid analgesic pain medicine increased substantially. There is now agreement that overprescribing of opioid analgesics occurs but is still unclear in the literature where this takes place and the exact circumstances when prescriptions are inappropriate.
• There has been a drastic reduction in opioid analgesic prescribing and overdose, but it has also resulted in sometimes making it difficult for patients with legitimate pain to receive pain relief.
• Abuse in the healthcare system has resulted in increasing barriers to access; for some, increasing difficulty finding health professionals willing or able to prescribe pain medication.
• Opioid analgesic prescribing has also declined in Florida.
• Worldwide, the consumption of opioid analgesics has substantially increased over the last 20 years. 

Opioid Overdose

• Nationally, opioid-related overdose fatalities are decreasing; peaking in 2011 and dropping since.
• In Florida, fatalities from illicit drugs have increased; whereas there has been a decrease in prescription overdose fatalities.
• Opioid analgesic fatalities often occur with co-ingestion of benzodiazepines, e.g., diazepam. 

Controlled Substance Use And Addiction/Use Disorder

Use disorder of prescription drugs has become a common problem. Those afflicted may not fit the profile of an individual addicted to street drugs. They are often individuals with jobs and chronic pain syndromes.  For multiple reasons, they may have sought self-medication to control the pain while maintaining their lifestyles. Since the societal view on using prescription drugs is that it is normal, access may be easier and safer than obtaining illicit drugs and medications may be covered under insurance, more and more people chose to figure out ways to obtain prescription drugs over the use of illicit drugs.

Prescription drug use disorder is more common in some demographic populations than others. It is a more common problem with:

• Individuals that use opioids inappropriately
• Those who regularly use opioids
• Those that use alcohol or tobacco
• Woman tend to abuse sedatives and tranquilizers

Illicit drug use is growing. In the United States, since the clamping down on prescription drug use, heroin use has increased dramatically.  Heroin used to be a rare problem, but as drug enforcement agencies clamped down on prescription abuse, those addicted turned to Schedule I drugs such as heroin. Individuals may also move from abusing Schedule II prescription drugs to abusing Schedule I illicit drugs.  Those with use disorder tend to follow the path of least resistance. If unable to easily obtain prescription drugs they turn to illicit drugs or vice versa.

Often patients are not appropriately educated on the addictive potential of controlled a substance such as a benzodiazepine or opioid. They are not aware of the danger if prescription renewals are easily accessible, especially if they see more than one prescriber.

Of those patients receiving treatment in an emergency department, some are actually seeking additional medication to supplement their current consumption of opioids. Studies have found of those patients prescribed opioids in an emergency setting, 5-10% are already consuming opioid medications from other prescribers. Many states have made this problem less prevalent by instituting statewide reporting of controlled substances prescriptions.

Pain is a common reason patients seek medical care. Pain occurs due to both emotional and sensory inputs and has acute or chronic components. Acute pain has associations with the sympathetic nervous system with physical findings that included an elevated heart rate, respiratory rate, and blood pressure. Pupillary dilation and diaphoresis may be evident.

Chronic pain usually does not involve sympathetic and may be associated with depression, fatigue, and loss of appetite and libido.

Acute Pain

Typically occurs in response to acute tissue injury, results from activation of peripheral pain receptors and specific A-delta and C sensory nerve fibers (nociceptors).

Chronic Pain

Typically occurs in response to ongoing tissue injury is thought to be caused by persistent activation of A-delta and C sensory fibers. The severity of tissue injury does not generally predict the severity of the pain. Chronic pain may result from damage or dysfunction of the peripheral or central nervous system causing neuropathic pain.

Nociceptive Pain

Nociceptive pain can be somatic or visceral. 

Somatic pain receptor stimulation produces dull or sharp local pain; burning is uncommon unless the skin or subcutaneous issues are involved.  Locations of these receptors include the skin, fascia, subcutaneous tissues, periosteum, endosteum, and joint capsules. 

Visceral pain receptors result in pain due to an injury of organ capsules and connective tissue. Pain can be localized or sharp. Visceral pain as a result of obstruction of a hollow organ is poorly localized, deep, and cramping and possibly referred to remote cutaneous sites. 

Pain Modulation and Transmission of Pain

Pain fibers enter the spinal canal and the spinal cord at the dorsal root ganglia and then synapse in the dorsal horn. Fibers cross to the other side and up the lateral columns to the thalamus and then to the cerebral cortex.

Repeat stimulus from a chronic painful condition may sensitize neurons in the dorsal horn of the spinal cord. As a result, a lesser peripheral stimulus may cause pain. Peripheral nerves and nerves at other levels of the CNS may become sensitized, producing long-term synaptic changes in cortical receptive fields that exaggerate pain perception.

When tissue is injured, substances are released causing an inflammatory cascade which can sensitize peripheral nociceptors. These include chemical messengers such as serotonin, bradykinin, epinephrine, calcitonin gene-related protein, substance P, neurokinin A, and prostaglandin E2.

Pain signals are modulated at multiple points in both ascending and descending pathways by several neurochemical mediators, including by endorphins such as enkephalin and monoamines such as norepinephrine and serotonin. These mediators are thought to increase, sustain, shorten, or reduce the perception of and response to pain. They mediate the potential benefit of CNS-active drugs such as antidepressants, anticonvulsants, opioids, antidepressants, and membrane stabilizing agents that interact with specific receptors and neurochemicals in the treatment of chronic pain. 

Psychologic Factors Causing Pain

Psychogenic factors can modulate pain intensity. Emotion has a vital role in an individuals perception of pain. Patients in chronic pain have a high degree of psychologic distress, often suffering from anxiety and depression. Patients with poorly explained pain may be incorrectly diagnosed with a psychiatric disorder rather than a legitimate underlying cause of the pain and are inappropriate denied pain relief, exacerbating the cycle of anxiety and depression.

Acute and chronic pain may impair concentration, memory, and thought processes. Pain may be multifactorial. Often pain is due to both nociceptive components as well as neuropathic (due to nerve damage).

Psychologic factors may modulate pain. It affects how patients describe the pain and their response. The psychologic reaction to long-standing chronic pain interacts with CNS factors to induce changes in the perception of pain. Psychologic factors generate neural output that modulates neurotransmission along each of the pain pathways.