Prescription of Controlled Substances: Benefits and Risks

Etiology

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.[14] Chronic pain syndromes have associations with many long-term conditions and diseases.

Common Causes of Legitimate Pain

Neurologic and Systemic Diseases that Cause Pain

• Alcohol use disorder
• 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
• Polymyalgia rheumatica
• Polyneuropathies
• Polyradiculopathies
• Postherpetic neuralgia
• Rheumatoid arthritis
• Side effects of chemotherapy or radiation therapy
• Sjögren 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 a use disorder to a controlled substance to control the pain increases. Risk factors for a use disorder with 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 a 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 a use disorder, there is a greater chance the children will develop a use disorder.
• Individuals who engage in prescriber shopping 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-age
• No psychiatric history
• Relaxed personality
• Those that follow instructions

Epidemiology

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 annually, 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 to 12 months, and almost 50% have had pain longer than 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
• The 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, opioid analgesic prescribing is actually declining.
• Hydrocodone, methadone and fentanyl prescribing has decreased by as much as one-third since peaking in 2011.
• Before 1990, physicians rarely prescribed opioids for noncancer pain. Starting in the 1990s, physicians were encouraged to control pain as this was the "fifth vital sign." The use of opioid analgesic pain medicine increased substantially. The consensus is that overprescribing of opioid analgesics occurs, but it is still unclear in the literature where this occurs 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

The 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. As societal views normalize using prescription drugs, access may be easier and safer than obtaining illicit drugs. Since medications may be covered under insurance, more and more people choose 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
• Women who tend to abuse sedatives and tranquilizers

Illicit drug use is growing. In the United States, since the restrictions 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 substances such as benzodiazepines or opioids. They are not aware of the danger when 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 that of patients prescribed opioids in an emergency setting, 5% to 10% are already consuming opioid medications from other prescribers. Many states have made this problem less prevalent by instituting statewide reporting of controlled substance prescriptions.

Pathophysiology

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 include an elevated heart rate, respiratory rate, and blood pressure. Pupillary dilation and diaphoresis may be evident.

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

Acute Pain

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

Chronic Pain

It typically occurs in response to ongoing tissue injury and 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 resulting from obstruction of a hollow organ is poorly localized, deep, 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 pain 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 that 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 endogenous opioids such as methionine enkephalin and beta-endorphin, 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, and membrane-stabilizing agents that interact with specific receptors and neurochemicals in treating chronic pain. 

Psychologic Factors Causing Pain

Psychogenic factors can modulate pain intensity. Emotion has a vital role in an individual's perception of pain. Patients in chronic pain have a high degree of psychological 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 inappropriately 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 the 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 pain perception. Psychologic factors generate neural output that modulates neurotransmission along each pain pathway.

Histopathology

Chronic pain and opioids generally do not cause any specific histopathology in and of themselves. However, there is a diversity of histopathologic changes that can occur in the presence of improper/recreational parenteral administration of opioids. There may be chronic tissue damage present due to the original assault.[15]

Toxicokinetics

How each person processes a drug, including the rate of chemical absorption and what occurs to excrete and metabolize the compound once it has entered the body, is highly variable among individuals. Further, it may change with the degree and years of use.

Use disorder is a biological condition secondary to various environmental and genetic factors. Each human metabolizes drugs differently, and depending on their body's response; they may have little or no ability to discontinue the use of a drug.

History and Physical

For prescribers, it may be difficult to distinguish legitimate pain from drug-seeking behavior. Pain is often difficult to assess because patients may be impaired, and self-reporting may be inaccurate or difficult to obtain. The astute clinicians should rely on a combination of taking an accurate history, physical, and observation-based assessment.

Signs of Pain

• Activity changes: Appetite, increased fatigue, increased alcohol consumption, routines, and increased sleep.

• Facial expressions: Frowning, grimacing, and rapid blinking

• Body movements: Guarding, fidgeting, inactivity, motor restlessness, pacing, rigidity, rocking, and muscle tension

• Interpersonal interaction changes: Aggression, diminished sex drive, disruptive behavior, irritability, resisting care, and being withdrawn

• Mental status change: Anxiety, crying, confusion, depression, distress, irritability, and suicidal thoughts

• Verbalizations: Calling out, "I hurt everywhere," requesting help, sighing, and verbal abuse

Symptoms of Pain

• Diaphoresis

• Hypertension

• Pupil dilation

• Tachycardia

• Tachypnea 

Pain Evaluation Questions

• Character - A description of how the pain feels (dull, pinching, pounding, sharp, shooting, throbbing, pounding, stinging, burning).

• Radiation - Does the pain move anywhere?

• Site - Where is the pain? Where does it hurt?

• Onset - When did the pain start?

• Progression - Has the pain gotten worse or better since it started?

• Duration - For how long have you had the pain? Is it episodic?

• Severity - What is the pain severity (1 to 10)?

• Aggravating factors - Does anything make it worse, such as movement or a position?

• Relieving factors - Does anything you do or not do make the pain better? What treatments have you tried?

• Associative factors - The clinician should query other relevant questions from a review of systems based on the patient complaint.

Signs and Symptoms of Drug-seeking Behavior and Diversion

A common method to evaluate whether a patient is taking or misusing opioids is a random urine drug screen. Studies show that as high as 25% of patients prescribed opioids will randomly test negative. Patients discontinue opioid use due to remission of pain, side effects, lack of efficacy, and in some instances, opportunities to sell their medications.

Behaviors suggesting opioid drug use disorder

• Aggressive demand for more drugs
• Forging prescriptions
• Increased alcohol use and lack of control
• Increasing dose without permission
• Injecting or inhaling drugs prescribed for oral use
• Obtaining drugs from illegitimate sources
• Obtaining opioids from other providers
• Prescription loss
• Refusing to decrease pain medication dosage when stabilized
• Resisting medication change
• Requesting early refills
• Requesting specific medications
• Selling drugs
• Sharing prescriptions
• Stockpiling medications
• Using illegal drugs 

Evaluation

Evaluating a patient needing opioid analgesics requires a complete history, physical examination, laboratory, and radiographic studies. Depending on the circumstances, consultation with psychiatry should be a consideration, along with addiction experts, physical therapy, and occupational therapy.[16]

The clinicians must have a complete understanding of the patient's primary disease and any issues regarding the evaluation of proper use, potential side effects, and effectiveness of opioid use for chronic pain.

Overview Of Safe Prescribing Assessment Guidelines

Health professionals are trained to prescribe pain medications; unfortunately, controlled substances are commonly misused. The following provides an overview of the requirements for the safe prescribing of controlled substances. A more detailed discussion follows.

• History
  • Review chief complaint
  • Obtain current and past medical conditions
  • Obtain a list of current and past medications prescribed and dosage
  • Obtain patients' past medical records
  • Review the pain rating scale
  • Review family history, including alcohol, drug (illicit and non-illicit), and mental health (depression assessment)
  • Review social history including alcohol, drug (illicit and non-illicit), tobacco, mental health (depression assessment) as well as dependents, education, employment, living situation, marital status, and legal issues
  • Review opioid abuse risk assessment
  • Review of state prescription drug program
• Physical - perform a head-to-toe detailed physical exam
• Obtain a urine drug test

Chronic Pain Assessment

Standard blood work and imaging are not indicated for chronic pain, but the clinician can order them when specific causes of pain are suspected. This can be on a case-by-case basis. In some cases, urine toxicology is ordered to monitor compliance and exclude nonprescription drugs.

Psychiatric disorders can amplify pain, signaling making symptoms of pain worse.[17] Furthermore, comorbid psychiatric disorders, such as major depressive disorder can significantly delay the diagnosis of pain disorders.[18] Major depressive disorder and generalized anxiety disorder are the most common comorbid conditions related to chronic pain. There are twice as many prescriptions for opioids prescribed each year to patients with underlying pain and a comorbid psychiatric disorder compared to patients without such comorbidity.[19] Intuitively, this makes sense. For example, a patient suffering from depression often complains of fatigue, sleep changes, loss of appetite, and decreased activity. These symptoms can make their pain worse over time. It is also crucial to realize patients with chronic pain are at an increased risk for suicide and suicidal ideation.[20][21]

Simultaneously screening for depression is recommended for patients with chronic pain. The Minnesota Multiphasic Personality Inventory-II (MMPI-2) or Beck's Depression Scale are the two most commonly used tools. The MMPI-2 has been used more frequently for patients with chronic pain.[22][23]

Addiction Risk Assessment

The clinician should consider information from the history and physical, family members, the state prescription monitoring program, and screening tools to assess the risk of developing an untoward behavioral response to opioids.[9][24][25] Patients can be stratified to three risk levels:

1. Low-risk: standard monitoring, vigilance, and care
   • Objective signs and symptoms, localizable physical pathology
   • Confirmatory testing such as physical exam findings, CT, MRI, etc.
   • No individual or family history of substance abuse
   • At most, mild medical or psychologic comorbidity
   • Age < 45
   • High pain tolerance
   • Active coping strategies
   • Willingness to participate in multimodal therapy
   • Attempting to function at normal levels
2. Moderate-risk: additional level of monitoring and more frequent provider contact
   • Significant pain
   • Defined pathology with objective signs and symptoms
   • Confirmatory testing such as physical exam findings, CT, MRI, etc.
   • Moderate psychologic problems controlled by therapy
   • Moderate comorbidities are well controlled by medical therapy and are not affected by opioids
   • Mild opioid tolerance but not hyperalgesia without addiction or physical dependence
   • Individual or family history of substance abuse
   • Pain involving more than three regions of the body
   • Moderate levels of pain acceptance
   • Active coping strategies
   • Willing to participate in multimodal therapy
   • Attempting to function at normal levels
3. High-risk: intensive and structured monitoring, frequent follow-up contact, consultation with an addiction psychiatrist, and limited monthly prescription of short-acting opioids
   • Significant widespread pain
   • No objective signs and symptoms
   • Pain involves more than three body regions
   • Divergent drug-related behavior
   • Individual or family history of addiction, dependency, diversion, hyperalgesia, substance abuse, or tolerance
   • Major psychologic problems
   • Age >45
   • HIV-related pain
   • High levels of pain exacerbation
   • Poor coping strategies
   • Unwilling to participate in multimodal therapy
   • Not functioning at a normal lifestyle

Prescribing Opioids

Before prescribing opioids, complete a detailed patient history that includes:

• Indication requested for pain relief
• Location, nature, and intensity of pain
• Prior pain treatments and response
• Comorbid conditions
• Potential physical and psychological pain impact on the function
• Family support, employment, and housing
• Leisure activities, mood, sleep, substance use, and work
• Emotional, physical, or sexual abuse

When considering opioids, weigh the risks of abuse, addiction, adverse drug reactions, overdose, and physical dependence. If there are any special concerns, such as a history of substance abuse, consult a psychiatrist or addiction specialist. If current substance abuse, withhold prescribing until the patient is involved in an addiction treatment and monitoring program.

Assessment Tools [25]

Screening tools help determine the risk level and degree of monitoring and structure required for a treatment plan; however, their validity is not yet supported in the literature. Some examples of opioid tools include:

Brief Intervention Tool

Brief Intervention Tool is a 26-item "yes-no" questionnaire used to identify signs of opioid addiction or abuse. The items assess for problems related to drug use-related functional impairment.

CAGE, CAGE-AID, and CAGE-Opioid

CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consists of four questions designed to assess alcohol abuse. CAGE-AID and CAGE-OPIOID are revised versions to evaluate the likelihood of current substance abuse.[26]

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure is a 17-item patient self-reported assessment designed to identify abuse in chronic pain patients. It identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy.

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Tool

The Diagnosis, Intractability, Risk, and Efficacy is a clinician-rated questionnaire used to predict patient compliance with long-term opioid therapy. Patients scoring low are poor candidates for long-term opioids.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that evaluates feelings of calmness, depression, happiness, peacefulness, and nervousness in the past month. A low score indicates that the patient should be referred to a pain management specialist.

Opioid Risk Tool

The Opioid Risk Tool is a five-item assessment to evaluate for aberrant drug-related behavior. It categorizes the patient into low, medium, or high levels of risk for aberrant drug-related behaviors based on question responses concerning previous alcohol, drug abuse, psychologic disorders, and other risk factors.

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards, and the Joint Commission stress documentation from both a quality and medicolegal perspective. The Pain Assessment and Documentation Tool (PADT) was designed to help the clinician document appropriate information.

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a screen with questions addressing the history of alcohol or substance use, cravings, mood psychologic status, and stress. The SOAPP-R helps assess the risk level of aberrant drug-related behaviors and the monitoring level needed.

VIGIL

• Verification: Is this a responsible opioid user?
• Identification: Is the identity of this patient verifiable?
• Generalization: Do we agree on mutual responsibilities and expectations?
• Interpretation: Do I feel comfortable allowing this person to have controlled substances?
• Legalization: Am I acting legally and responsibly? 

Urine Drug Tests (UDT)

Urine drug tests evaluate the use of the medication prescribed and detect unsanctioned drug use. The CDC recommends drug testing before starting opioid therapy and at least annually.

One study suggests monitoring frequency based on risk level.[27] 

Testing is usually done with class-specific immunoassay drug panels; however, this may be followed with gas chromatography/mass spectrometry for specific metabolite detection. The test should identify the specific drug. If urine test results suggest aberrant opioid use, discuss the issue with a positive, supportive approach, and document the discussion.

Treatment / Management

Opioid analgesics should be prescribed for a limited period, typically several days to 3 to 4 weeks. The patient needs education on the risks and benefits of opioid treatment. Treatment goals should be set at the outset, including establishing the estimated time period, expected side effects, expected pain improvement, and avoiding more medication than prescribed without prior discussion with the provider. The therapy plan should include the drug selected, starting dosage, measures to track pain relief and associated therapies such as occupational or physical therapy.[28]

The initial patient dose should always be the lowest dose possible and, if necessary, gradually increase dose and frequency to achieve the desired effect. Dosing should be adjusted to achieve efficacy and tolerability. The patient should clearly understand the need for regular monitoring of progress and the need to frequently access the benefits and risks. The patient should be aware of complications such as constipation, fatigue, nausea, and risk of respiratory depression. The patient should make sure that only one prescriber should prescribe and monitor opioid analgesic therapy. Further, patients should understand that all prescribers need to be aware of opioid dosing so that other agents, such as CNS depressants, can be avoided, which may interact and cause additional respiratory depression.

When prescribing opioids, prescribers must be aware of the need for patient monitoring, equianalgesic dosing, and cross-tolerance. Prescribers need to consider the risks and benefits of short vs. long-acting/extended-release opioids.

All prescribers must be aware of federal and state opioid prescribing regulations.

Treatment Agreements and Informed Consent

Due to the inherent risks of opioids, the opioid prescription should include a treatment agreement or written informed consent for any treatment for more than a few days. Treatment agreements should include the following:

• Use disorder and misuse risks
• Drug interactions
• Physical dependence
• Motor impairment
• Short and long-term risks/benefits
• Side effects (constipation, rash, nausea, and respiratory depression)
• Tolerance

Prescribing practices should be stated, including:

• Frequency of refills
• Policy regarding early refills
• Procedure for lost or stolen medications

The agreement should also require the patient to limit opioid prescriptions to one physician and consent to random urine drug screens. Patient instruction should be to contact the prescriber for problems and make in-person appointments for refills. The agreement should discuss monitoring, the need for follow-up visits, storage, and disposal of opioids not used. The agreement should list potential reasons for the discontinuation of opioid therapy.

Overview Of Safe Treatment With or Without Controlled Substances

Generally, the provider should consider using a non-controlled substance to alleviate pain. However, if this fails, and the decision is made to prescribe a controlled substance, before beginning therapy, two important documents should be obtained:

1. Informed consent - should include the drug prescribed, risks (overdose, respiratory depression, dependence, drug interaction, death, and if the female is at risk of neonatal withdrawal syndrome), benefits (pain relief), desired goal or outcome, expected length, and follow-up care. Those goals should be collaborative.
2. Patient-provider agreement - This is signed by the patient and provider and includes responsibilities of the patient and provider, goals of controlled substance use, and the consequences of nonadherence with the treatment plan.
   • The first prescription is a trial with a determined follow-up appointment
   • Includes pill counts if needed
   • Refills and how they are handled
   • Use of a single provider for all controlled substances
   • Exit strategy when goals are achieved

Mild pain - start with acetaminophen or nonsteroidal anti-inflammatory drug, or in some cases, both. Whenever possible, consider alternative pain relief therapies, including physical therapy, massage, electrotherapy stimulation, Yoga, biofeedback, and acupuncture.

Moderate pain - start with a mild opioid such as codeine or tramadol. Also, consider supplemental alternative pain relief therapies.

Severe pain - start with a more potent opioid such as hydrocodone, hydromorphone, oxycodone, or morphine. Use immediate-release controlled substances with a half-life of 2 to 4 hours until the dose is stabilized. Adjust dose initially every 2-3 days. Extended-release or long-acting opioids with a half-life of 8-12 hours in the same family are added later. Also, consider supplemental alternative pain relief therapies.

Chronic Pain

Healthcare professionals who treat patients with chronic pain should understand best practices in opioid prescribing, approaches to pain assessment, pain management modalities, and appropriate use of opioids for pain control. Pharmacologic and nonpharmacologic approaches should be evaluated. Patients with moderate-to-severe chronic pain who have been assessed and treated with non-opioid therapy without adequate pain relief are candidates for opioid therapy. Initial treatment should be a trial of therapy, not a definitive course of treatment. The CDC has issued updated guidance on prescribing opioids for chronic pain. These guidelines address when to initiate or continue opioids for chronic pain, opioid selection, dosage, duration, follow-up, and discontinuation, assessing risk, and addressing opioid use harm.

Pain Referral

Recommendations are to refer a patient to pain management in the case of debilitating pain which is unresponsive to initial therapy. The pain may be located at multiple locations, requiring multimodal treatment or increases in dosages for adequate pain control or invasive procedures to control pain. Treatment of both pain and a comorbid psychiatric disorder leads to a more significant reduction of both pain and symptoms of the psychiatric disorder.[29] Pain may also worsen concurrent depression; thus, the treatment of pain has been demonstrated to improve the responses to the treatments for depression.[30] There are multiple pharmacological, adjunct, nonpharmacological, and interventional treatments for chronic, severe, and persistent pain. (B2)

Pharmacologic Options

The list of pharmacological options for chronic pain is extensive. This list includes non-opioid analgesics such as nonsteroidal anti-inflammatories (NSAIDs), acetaminophen, and aspirin. Medications such as tramadol, opioids, and antiepileptic drugs (gabapentin or pregabalin) can be useful. Furthermore, antidepressants such as tricyclic antidepressants and SNRIs, topical analgesics, muscle relaxers, N-methyl-d-aspartate (NMDA) receptor antagonists, and alpha 2 adrenergic agonists are also possible pharmacological therapies. 

Treatment response can differ between individuals, but treatment is typically done in a stepwise fashion to reduce the duration and dosage of opioid analgesics. However, there is no singular approach appropriate for treating pain in all patients.[31]

Major Pain Types and Treatment Options

Musculoskeletal

Chronic musculoskeletal pain is nociceptive pain. The treatment of such pain is in a stepwise approach but includes a combination of non-opioid analgesics, opioids, and nonpharmacological therapies. First-line therapy would be acetaminophen or NSAIDs. Both are effective for osteoarthritis and chronic back pain.[32][33][34] However, NSAIDs are relatively contraindicated in patients with a history of heart disease or myocardial infarction, renal disease, or patients on anticoagulation or with a history of ulcers.[35][36] There is limited evidence of which NSAID to use over another. One nonsteroidal anti-inflammatory pharmacological agent may have a limited effect on a patient's pain, while another may provide adequate pain relief. The recommendations are to try different agents before moving on to opioid analgesics.[37] Failure to achieve appropriate pain relief with either acetaminophen or NSAIDs can lead to considering opioid analgesic treatment. (A1)

Opioids are considered a second-line option; however, they may be warranted for pain management for patients with severe persistent pain or neuropathic pain secondary to malignancy.[38] There have been conflicting results on the use of opioids in neuropathic pain. However, for both short-term and intermediate use, opioids are often used to treat neuropathic pain.[39] Opioid therapy should only start with extreme caution for patients with chronic musculoskeletal pain.[40] Side effects of opioids are significant and frequent and may include opioid-induced hyperalgesia, constipation, dependence, and sedation. For chronic musculoskeletal pain they are not superior to non-opioid analgesics.[41][42](A1)

Administration of opioid analgesics should be reserved for when alternative pain medications have not provided adequate pain relief or are contraindicated and when pain impacts the patient's quality of life. The potential benefits outweigh the short and long-term effects of opioid therapy. The patient must make an informed choice before starting opioid treatment after discussing the risks, benefits, and alternatives to opioids.[41][43][44] Patients taking opioids at greater than 100 morphine milligram equivalents per day are at significantly increased risk of side effects. Side effects of opioids such as respiratory compromise will increase as the dosages increase. Patients with chronic pain could benefit from a therapy program designed to wean them from opioid analgesics to a safer dosage.[45][46] Long-acting opioids should only be used over short-acting opioids in the setting of disabling pain, causing severe impairment to quality of life.[47](A1)

There is an estimated 78 percent risk of an adverse reaction to opioids, such as constipation or nausea, while there is a 7.5 percent risk of developing a severe adverse reaction ranging from immunosuppression to respiratory depression.[48] Patients with chronic pain who meet the criteria for the diagnosis of opioid use disorder should receive the option of buprenorphine to treat their chronic pain. Buprenorphine is a considerably better alternative for patients with very high daily morphine equivalents who have failed to achieve adequate analgesia.(B3)

Different types of pain also warrant different treatments. For example, chronic musculoskeletal back pain would be treated differently from severe diabetic neuropathy. A combination of multiple pharmacological therapies is often necessary to treat neuropathic pain. Less than 50% of patients with neuropathic pain will achieve adequate pain relief with a single agent.[49] Adjunctive topical therapy, such as lidocaine or capsaicin cream, can also be utilized.[50][51](A1)

Neuropathic

The initial treatment of neuropathic is often with gabapentin or pregabalin. These are calcium channel alpha 2-delta ligands. They are indicated for postherpetic neuralgia, diabetic neuropathy, and mixed neuropathy.[52] There is limited evidence in using other antiepileptic medications to treat chronic pain, where many of these, such as lamotrigine, have a more significant side effect profile. The exception is carbamazepine in treating trigeminal neuralgia and other types of chronic neuropathic pain.[53][54](A1)

Alternatively, antidepressants such as dual reuptake inhibitors of serotonin and norepinephrine (SNRI) or tricyclic antidepressants (TCA) can is an option. Antidepressants are beneficial in treating neuropathic pain, central pain syndromes, and chronic musculoskeletal pain. For neuropathic pain, antidepressants have demonstrated a 50 percent reduction in pain. Fifty percent is a significant reduction, considering the average decrease in pain from various pain treatments is 30%.[55][56](A1)

The serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine is a useful treatment for treating chronic pain, osteoarthritis, and fibromyalgia.[57] Furthermore, the efficacy of duloxetine in the treatment of comorbid depression is comparable to other antidepressants.[58][55] Venlafaxine is an effective treatment for neuropathic pain, as well.[59] A TCA can also be utilized, such as nortriptyline. TCA medications may require six to eight weeks to achieve their desired effect.[38](A1)

Adjunctive topical agents such as topical lidocaine are a useful treatment for neuropathic pain and allodynia, as in postherpetic neuralgia.[60][61] Topical NSAIDs have been shown to improve acute musculoskeletal pain, such as a strain, but are less effective in chronic pain. Yet, topical NSAIDs are more effective than controls in treating pain related to knee osteoarthritis.[62][63] Separately, topical capsaicin cream is an option for chronic neuropathic or musculoskeletal pain unresponsive to other treatments.[64] Botulinum toxin has also demonstrated effectiveness in the treatment of postherpetic neuralgia.[65] The use of cannabis is also an area of interest in pain research. There is some evidence that medical marijuana can effectively treat neuropathic pain, while the evidence is currently limited in treating other types of chronic pain.[66](A1)

Additional Nonpharmacologic Options

The list of nonpharmacological therapies for chronic pain is extensive. Nonpharmacological options include heat and cold therapy, cognitive behavioral therapy, relaxation therapy, biofeedback, group counseling, ultrasound stimulation, acupuncture, aerobic exercise, chiropractic, physical therapy, osteopathic manipulative medicine, occupational therapy, and TENS units. Interventional techniques can also be utilized in the treatment of chronic pain. Spinal cord stimulation, epidural steroid injections, radiofrequency nerve ablations, botulinum toxin injections, nerve blocks, trigger point injections, and intrathecal pain pumps are some procedures and techniques commonly used to combat chronic pain. TENS units' efficacy has been variable, and the results of TENS units for chronic pain management are inconclusive.[67] Deep brain stimulation is for post-stroke and facial pain as well as severe, intractable pain where other treatments have failed.[68] There is limited evidence of interventional approaches to pain management. For refractory pain, implantable intrathecal delivery systems are an option for patients who have exhausted all other options. Cognitive-behavioral has been found to be particularly helpful for pelvic pain syndromes.[69] (A1)

Spinal cord stimulators are an option for patients with chronic pain who have failed other conservative approaches. Most commonly, spinal cord stimulators are placed following failed back surgery but can also be an option for other causes of chronic pain such as complex regional pain syndrome, painful peripheral vascular disease, intractable angina, painful diabetic neuropathy, and visceral abdominal and perineal pain.[70][71][72][73][74] Spinal cord stimulators have shown a 50% reduction in pain compared to continued medical therapy.[75](A1)

Differential Diagnosis

Examples of conditions that may require acute or chronic opioid analgesic use include:

• Abdominal epilepsy
• Abdominal migraines
• Achilles tendon injuries
• Adhesive capsulitis
• Adenomyosis
• Adhesions
• Adnexal cysts
• Brachial neuritis
• Cancer
• Carpal tunnel syndrome
• Cervical disc disease
• Cervical myofascial pain
• Cervical spondylosis
• Cervical sprain and strain
• Complex regional pain syndromes
• Cervical stenosis
• Chronic pelvic pain
• Chronic visceral pain
• Chronic fatigue syndrome
• Colitis
• Dyspareunia
• Endocervical polyps
• Endometriosis
• Fibromyalgia
• Gastrointestinal problems
• Hernias
• Irritable bowel syndrome
• Lateral epicondylitis
• Lumbar degenerative disk disease
• Lumbar facet arthropathy
• Lumbar spondylolysis and lumbar spondylolisthesis
• Mechanical back strain
• Medial epicondylitis
• Mononeuropathy and nerve entrapment
• Morton neuroma
• Myofascial pain
• Neoplasia of the spinal cord
• Neoplastic brachia plexopathy
• Neoplastic lumbosacral plexopathy
• Osteoarthritis
• Osteoporosis
• Ovarian retention syndrome
• Pelvic floor pain syndrome
• Piriformis syndrome
• Radiation-induced brachial plexopathy
• Radiation-induced lumbosacral plexopathy
• Rectus abdominis pain
• Rotator cuff disease
• Pelvic varicosities
• Plantar fasciitis
• Reproductive system disorders
• Spasticity
• Substance abuse
• Thoracic outlet syndrome
• Traumatic brachial plexopathy
• Trochanteric bursitis
• Uterine leiomyomas
• Urinary system disorders
• Urolithiasis
• Vulvodynia 

Treatment Planning

Opioid analgesics should be prescribed for a limited period, typically several days to 3-4 weeks. Patient education on the risks and benefits of opioid analgesic treatment should always be a feature of opioid prescribing. The goal of treatment should be defined at the outset, including establishing the estimated period for opioid therapy, expected side effects, expected pain improvement, and avoidance of using more medication than prescribed without prior discussion with the provider. The treatment plan should include the drug selected, starting dosage, measures to track pain relief, and associated therapies such as occupational or physical therapy, which can help decrease pain sensation.

Opioid therapy should begin as a trial for a pre-defined period, usually less than 30 days. Treatment goals should be established prior to the initiation of opioid therapy. These include the level of relief of pain, anxiety, depression, and the return of function while avoiding unnecessary opioid use. The plan should include therapy selection, progress measures, and additional consultations, evaluations, referrals, and therapies. The provider should:

• Start at the lowest possible dose and then titrate to effect
• Start with short-acting opioid formulations
• Discuss the need for frequent risk/benefit assessments
• Be instructed in the signs and symptoms of respiratory depression
• Reassess risk/benefit with each dose increase
• Decisions to titrate dose to 90 mg or more morphine equivalent dose should be justified
• Be knowledgeable of federal and state opioid prescribing regulations
• Be knowledgeable of patient monitoring, equianalgesic dosing, and cross-tolerance with opioid conversion
• Augment treatment with nonopioid or, if necessary immediate-release opioids over long-acting opioids
• Taper opioid dose whenever possible

Consent and Treatment

The patient must consent to the course of therapy and understand all implications of their medical regimen.[9]

The opioid prescription should include documented informed consent and a treatment agreement addressing:

• Drug interactions
• Physical dependence
• Side effects
• Tolerance
• Physical dependence
• Driving and motor skill impairment
• Limited evidence of long-term benefit
• Addiction, dependence, misuse
• Risk/benefit profile of the drug prescribed
• Signs/symptoms of overdose

Prescribing policies should be clearly described, including policies regarding the number and frequency of refills and procedures for lost or stolen medications.

Patient and Physician Treatment Agreement

• The patient should agree to use medications safely, avoid "prescriber shopping," and consent to urine drug testing.
• The prescriber should agree to address problems, follow-up visits, and scheduled refills.

Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include follow-up visits, monitoring, and safe storage and disposal of unused drugs. If the patient does not speak English, an interpreter should be used.

Discontinuing Opioid Therapy

Discontinuing opioid therapy should be based on a physician-patient discussion. Opioids should be discontinued when the pain has resolved, side effects develop, analgesia is inadequate, quality of life is not improved, deterioration of function, or evidence of aberrant medication use. Opioids should be tapered slowly, and an addiction specialist should manage withdrawal.

Toxicity and Adverse Effect Management

The toxicities of prescribed opioid analgesics are avoidable with appropriate daily dosing, and opioid analgesics are not combined with other central nervous system depressants, e.g., ethanol, diazepam, and phenobarbital.[76]

Constipation is not an uncommon side effect of opioid analgesics, but this is manageable with the careful use of laxatives. If laxative treatment is ineffective, then drugs like methylnaltrexone can help relieve constipation while maintaining pain control with the opioid analgesic, e.g., morphine.

Adverse Reactions to Opioids

Common adverse reactions include drowsiness, respiratory depression, confusion, dizziness, nausea/vomiting, headache, fatigue, pruritus, pinpoint pupils, constipation, and urinary retention. Because opioids induce euphoria at higher doses than prescribed, these drugs are at high risk for abuse and addiction. Long-term drug tolerance, hyperalgesia, or increased sensitivity to pain caused by damage to nociceptors or peripheral nerves may occur.

Depressants 

Hypnotics, sedatives, and tranquilizers treat anxiety and sleep disorders. These drugs increase the inhibitory activity of the neurotransmitter gamma-aminobutyric acid by inhibiting overall brain activity, producing a calming effect. Examples of depressants include:

Anxiety

Benzodiazepines are schedule IV  medications and include drugs such as alprazolam, clonazepam, diazepam, estazolam, and triazolam. They are used to treat anxiety, stress reactions, muscle spasms, and sleep disorders. They should be used short-term with caution as they have a high risk of addiction, dependence, and tolerance. The combination of benzodiazepines and opioids should be avoided due to the potential for addiction and respiratory depression.

All CNS depressants can cause confusion, drowsiness, and poor coordination. Avoid stopping these medications abruptly due to the risk of dangerous or fatal withdrawal symptoms or seizures. Benzodiazepine overdose is treated with a benzodiazepine antagonist, flumazenil, which can be administered via IV and provides rapid reversal.

For anxiety treatment, there are available options that are less risky such as buspirone, which binds to serotonin and dopamine D2 receptors. It causes minimal drowsiness and has less abuse potential.

Sleep

Whenever possible, prescribers should select non-benzodiazepine sleep medications such as eszopiclone, zolpidem, and zaleplon, which act on GABA type A receptors in the brain but with fewer side effects and less risk of dependence, and they are schedule IV. Other options include melatonin and ramelteon.

Stimulants

Stimulants often abused include dextroamphetamine, methamphetamine, and methylphenidate. They work by enhancing the effects of the neurotransmitters norepinephrine and dopamine in the brain. While stimulants increase alertness, cognition, energy, and motivation, they also induce vascular constriction resulting in elevated heart rate and blood pressure, increased respiratory rate, dilated airway, elevated blood glucose, and insomnia. They are used to treat attention-deficit hyperactivity disorder, narcolepsy, and rarely depression. Misuse can cause euphoria due to increased dopamine activity in the brain. Abrupt withdrawal can cause depression, fatigue, and insomnia. Abuse or overdose may cause hostility, paranoia, psychosis, hyperthermia, arrhythmias, cardiovascular arrest, or seizures. They are classified as schedule II drugs.

A slightly safer alternative is modafinil, which works to block the reuptake of dopamine and other neurotransmitters. It has a slightly safer profile and is classified as schedule IV.

The American Society of Interventional Pain Physicians guidelines recommends monitoring opioid adherence, abuse, and nonadherence through urine drug tests and monitoring programs.

The treatment plan for opioid use in chronic pain should include frequent assessment of pain level, origin, and function. If there is a dosage change or agent, the frequency of patient visits should be increased. Chronic response to opioids should be monitored by evaluating the "5 As."

• Affect
• Aberrant drug-related behaviors
• Activities of daily living
• Adverse or side effects
• Analgesia

Signs and symptoms, if present, that suggests treatment goals are not being achieved include:

• Decreased appetite
• Excessive sleeping or day/night reversal
• Impaired function
• Inability to concentrate
• Mood volatility
• Lack of involvement with others
• Lack of re-engaging in life
• Lack of hygiene

The decision to change, continue, or terminate opioid therapy is based on achieving treatment objectives without adverse effects. Physicians, wherever possible, should work with pharmacists. 

Acute Overdose Management

Accidental or deliberate overdose is always a risk factor in patients taking opioids. The patient and family should be instructed in the signs and symptoms of an overdose and basic emergency management until paramedics' arrival.[77]

The immediate response to overdose management is to secure the airway and breathing; however, survival is heavily dependent upon the rapid administration of an opioid antagonist. Many states allow naloxone distribution to the public. Licensed healthcare providers may prescribe opioid antagonists for at-risk individuals, relatives, or caregivers. Emergency medical service personnel, peace officers, and firefighters also have the drug available.

While opioid antagonists such as naloxone, naltrexone, and nalmefene are available, acute overdoses are usually treated with naloxone as it quickly reverses opioid-related respiratory depression. Naloxone competes with opioids at receptor sites in the brain stem, reversing desensitization to carbon dioxide and preventing respiratory failure. 

The naloxone dose is 0.4 to 2 mg administered intravenously, intramuscularly, or subcutaneously. The dose may be repeated every 2 to 3 minutes. Naloxone is available in pre-filled auto-injection devices. Advanced Cardiac Life Support protocols should be continued while naloxone is being administered. Naloxone is also available in a nasally administered dosage form.

Prognosis

Physicians should carefully evaluate and treat patients for acute pain syndromes and use opioid analgesics at the appropriate dose and only on a short-term basis. Those patients requiring long-term pain control should obtain a referral to a pain management specialist.

Current chronic pain treatments can result in an estimated 30% decrease in a patient's pain scores.[31] A thirty percent reduction in pain can significantly improve a patient's function and quality of life.[78] However, the long-term prognosis for patients with chronic pain demonstrates reduced function and quality of life. Improved outcomes are possible in patients with chronic pain and improve with the treatment of comorbid psychiatric illness. Chronic pain increases patient morbidity and mortality and increases rates of chronic disease and obesity. Patients with chronic pain are also at a significantly increased risk for suicide compared to the regular population.

Spinal cord stimulation results in inadequate pain relief in about 50% of patients. Tolerance can also occur in up to 20 to 40 percent of patients. The effectiveness of spinal cord stimulation decreases over time.[79] Similarly, patients who develop chronic pain and are dependent on opioids often build tolerance over time. As the amount of morphine milligram equivalents increases, the patient's morbidity and mortality also increase.

Ultimately, prevention is critical in the treatment of chronic pain. If acute and subacute pain receives appropriate treatment and chronic pain can be avoided, the patient will have limited impacts on their quality of life. 

Complications

In the United States, two of the critical complications and public health concerns of opioid analgesics are overdoses and opioid use disorder.

Chronic pain leads to significantly decreased quality of life, reduced productivity, lost wages, worsening chronic disease, and psychiatric disorders such as depression, anxiety, and substance abuse disorders. Patients with chronic pain also have a significantly increased risk for suicide and suicidal ideation.

Many medications often used to treat chronic pain have potential risks and side effects, and possible complications associated with their use.

Acetaminophen is a standard pharmacological therapy for patients with chronic pain. It is taken either as a single agent or in combination with an opioid analgesic. The hepatotoxicity occurs with acetaminophen when exceeding four grams per day.[80] It is the most common cause of acute liver failure in the United States.[81] Furthermore, hepatotoxicity can occur at therapeutic doses for patients with chronic liver disease.[82]

Frequently used adjunct medications such as gabapentin or pregabalin can cause sedation, swelling, mood changes, confusion, and respiratory depression in older patients who require additional analgesics.[83] These agents require caution in elderly patients with painful diabetic neuropathy. Also, gabapentin or pregabalin, combined with opioid analgesics, has been shown to increase the rate of patient mortality.[84]

Duloxetine can cause mood changes, headaches, nausea, and other possible side effects and should be avoided in patients with a history of kidney or liver disease.

Feared complications of opioid therapy include addiction as well as overdose resulting in respiratory compromise. However, opioid-induced hyperalgesia is also a significant concern. Patients become more sensitive to painful stimuli while on chronic opioids.[85] The long-term risks and side effects of opioids include constipation, tolerance, dependence, nausea, dyspepsia, arrhythmia (methadone treatment QTc prolongation), and opioid-induced endocrine dysfunction, which can result in amenorrhea, impotence, gynecomastia, and decreased energy and libido. Also, there appears to be a dose-dependent risk of opioid overdose with increasing daily milligram morphine equivalents.

Complication rates for spinal could stimulators are high, ranging from five to 40%.[86][87] Lead migration occurs most commonly, causing inadequate pain relief and requiring revision and anchoring.[88][89] Lead movement often occurs in the cervical region of the spinal cord, given an increased range of motion of the cervical vertebra.[90][91] Spinal cord stimulator lead fracture can occur in up to 9% of placements.[92][93] Seromas are also very common and may require surgical incision and drainage.[94][86] The risk of infection following a spinal cord stimulator placement is between 2.5 and 12 percent.[95][96] Lastly, direct spinal cord trauma could occur. The most significant infectious complication would be a spinal cord abscess. A dural puncture can cause a post-dural headache in up to 70% of patients.[97][98][94] A spinal epidural hematoma is the most significant adverse to spinal cord stimulator placement. This emergency would require immediate neurosurgical decompression of the hematoma. The incidence of a spinal epidural hematoma is 0.71%.[99]

Drug Diversion and Drug Seeking

Unfortunately, some individuals seek prescribed opioids for illicit purposes due to addiction or financial gain. Prescription opioids may be obtained from a friend or relative, purchased from a black market drug dealer, obtained by prescriber shopping and acquiring drugs from multiple prescribers, and theft from clinics, hospitals, or pharmacies.[24]

• Aggressive demands for more opioids
• Asking for opioids by name
• Behaviors suggesting opioid use disorder
• Forged prescriptions
• Increased alcohol use
• Increasing medication dose without provider permission
• Injecting oral medications
• Obtaining medications from nonmedical sources
• Obtaining opioids from multiple providers
• Prescription loss or theft
• Reluctance to decrease opioid dosing
• Resisting medication change
• Requesting early refills
• Selling prescriptions
• Sharing or borrowing similar medications
• Stockpiling medications
• Unsanctioned dose escalation
• Using illegal drugs
• Using pain medications to treat other symptoms

Drug Diversion Interventions

Prescribers and dispensers can take several precautions to avoid drug diversion. Some approaches include:

• Communication among providers and pharmacies to prevent "prescriber shopping"
• Educate patients on the dangers of sharing opioids 
• Encourage patients to keep opioid medications in a private place
• Encourage patients to refrain from public disclosure of opioid use
• Report patient prescribing to a state-level central database if available

If a patient is suspected of drug-seeking or diversion, consider the following actions:

• Inquire about prescription and illicit drug use
• Obtain a urine drug screen
• Perform a thorough examination
• Perform pill counting
• Prescribe smaller quantities of the opioid

If a patient is abusing prescribed opioids, this is a violation of the treatment agreement. The provider may then choose to discharge the patient from their practice. If the relationship is terminated, the provider must do it legally. The provider should avoid patient abandonment, ending a relationship with a patient without considering the continuity of care, and without providing notice to the patient. To avoid abandonment charges, the patient must be given enough advanced warning to allow them to secure another physician and facilitate the transfer of care.

Patients with a substance misuse problem or addiction should be referred to a pain specialist. Theft or loss of controlled substances should be reported to the Drug Enforcement Administration. The activity should be documented and reported to law enforcement if drug diversion has occurred.