Prescription of Controlled Substances: Benefits and Risks

Etiology

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 neurological 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

Neurological 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
• Adverse effects of chemotherapy or radiation therapy
• Sjögren syndrome
• Spinal stenosis
• Systemic lupus erythematosus
• 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 Factors Contributing to the 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 substance use disorder to a controlled substance to control the pain increases. Risk factors for a substance use disorder with a pain medication include:

• Age
• Life circumstances
• Medical problems
• Physical problems

Factors that increase the risk of developing substance use disorder include:

• If an individual uses drugs to stay awake or sleep, they are at increased risk of developing a substance use disorder.
• If an individual undergoes exposure to other individuals with a substance use disorder, they are at a higher risk of developing substance use disorder.
• If a parent has a substance use disorder, there is a greater chance that the children may develop a substance use disorder.
• Individuals who engage in prescriber shopping are at increased risk of substance 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 substance use disorder include:

• Middle age
• No history of psychiatric illness
• Relaxed personality
• Adherence to prescribed instructions

Epidemiology

Acute and chronic pain are significant problems in the United States and worldwide. In the United States alone, it affects more than 100 million Americans annually. The evaluation and treatment of pain costs over 600 billion dollars annually, including the impact on individuals unable to work due to pain syndromes.

Pain Frequency

• Pain is one of the leading reasons individuals receive federal and private disability benefits..
• Pain syndromes affect as much as 50% of the United States population at some point in their lifetime.
• Among individuals older than 21, approximately 10% have experienced pain for 3 to 12 months, and almost 50% have had pain longer than 1 year. Nearly 50% report their pain is uncontrolled.
• Over 5 million Americans are receiving long-term opioid analgesics for chronic pain, and for many, the pain is significantly disabling.

Factors Contributing to the Rising Frequency of Acute and Chronic Pain

The prevalence of both acute and chronic pain is believed to be increasing due to several contributing factors:

• 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 postoperative 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 personnel and civilians with traumatic conditions has increased, despite increased pain during recovery.

Frequency of Opioid-Related Concerns

Frequency of opioid prescribing and consumption:

• Even though the lay literature reports that opioid prescribing is on the rise, opioid analgesic prescribing is declining.
• Prescriptions for hydrocodone, methadone, and fentanyl have decreased by as much as one-third since peaking in 2011.
• Before the 1990s, clinicians rarely prescribed opioids for noncancer pain. Beginning in the 1990s, clinicians were encouraged to control pain, as it was considered 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.
• Although opioid prescribing and overdose rates have declined significantly, this reduction has, at times, made it more difficult for patients with legitimate pain to access adequate pain relief.
• Abuse within the healthcare system has led to increasing barriers to access, making it more difficult for some patients to find healthcare 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 have been decreasing since peaking in 2011.
• 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, such as diazepam.

Controlled Substance Use and Addiction/Substance Use Disorder

The substance use disorder of prescription drugs has become a common problem. Individuals affected may not fit the profile of an individual addicted to street drugs. These individuals are often employed and suffer from chronic pain syndromes. For multiple reasons, they may have sought self-medication to manage their pain while maintaining their lifestyles. As societal views normalize using prescription drugs, access may be easier and safer than obtaining illicit drugs. Furthermore, since many prescription medications may be covered under insurance, an increasing number of people choose to figure out ways to obtain prescription drugs over the use of illicit drugs.

Prescription drug use disorder tends to be more common among certain demographic groups, including:

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

Illicit drug use is on the rise. In the United States, following the restrictions on prescription drugs, the use of heroin has increased significantly. Heroin use was previously uncommon; however, as drug enforcement agencies intensified efforts to address prescription drug abuse, many individuals with a substance use disorder turned to Schedule I drugs such as heroin. Individuals may also move from abusing Schedule II prescription drugs to abusing Schedule I illicit drugs. Individuals with a substance use disorder tend to follow the path of least resistance. When they are unable to obtain prescription drugs easily, 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. These patients are not aware of the danger when prescription renewals are easily accessible, especially if they see more than one prescriber.

Of 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 reduced the prevalence of this problem by instituting statewide reporting of controlled substance prescriptions.

Pathophysiology

Pain is a common reason patients seek medical care. Pain arises from both emotional and sensory inputs, encompassing acute and chronic components.

Acute Pain

Acute pain typically occurs in response to acute tissue injury and is mediated by the activation of peripheral pain receptors and specific sensory nerve fibers, including A-delta and C nociceptors.

Acute pain is associated 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

Chronic Pain typically occurs in response to ongoing tissue injury and is believed 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 CNS, causing neuropathic pain. Chronic pain typically does not involve the sympathetic nervous system and may be associated with depression, fatigue, loss of appetite, and loss of libido.

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 tissue is 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 to the 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

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.

Repeated stimuli 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.

Tissue injury triggers the release of various substances that initiate an inflammatory cascade, sensitizing peripheral nociceptors. These chemical mediators include 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 believed 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. 

Psychological 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, leading to inappropriately denied pain relief and exacerbating the cycle of anxiety and depression.

Acute and chronic pain may impair concentration, memory, and thought processes. Pain may be multifactorial, typically involving both nociceptive and neuropathic components (resulting from nerve damage).

Psychological factors may modulate pain, affecting how patients describe the pain and their response. The psychological reaction to long-standing chronic pain interacts with CNS factors to induce changes in pain perception. Psychological factors generate neural output that modulates neurotransmission along each pain pathway.

Histopathology

Chronic pain and opioids typically do not cause any specific histopathology changes on their own. However, improper or recreational parenteral administration of opioids can lead to a range of histopathologic alterations, including chronic tissue damage. There may be chronic tissue damage resulting from the initial injury.[15]

Toxicokinetics

The way each person processes a drug, including the rate of chemical absorption and the body's mechanisms for excreting and metabolizing the compound, varies significantly among individuals. Additionally, these processes can change based on the extent and duration of drug use.

Substance use disorder is a biological condition secondary to various environmental and genetic factors. Each individual metabolizes drugs differently, and depending on their body's response, some may find it very difficult or even impossible to stop using a drug.

History and Physical

For prescribers, distinguishing legitimate pain from drug-seeking behavior can be challenging. Pain is often difficult to assess because patients may be impaired, and self-reporting may be inaccurate or difficult to obtain. Astute clinicians should rely on a comprehensive evaluation that includes a detailed history, a thorough physical examination, and an 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: Statements, such as I hurt everywhere; requesting help; sighing; and verbal abuse

 Symptoms of Pain

• Diaphoresis
• Hypertension
• Pupil dilation
• Tachycardia
• Tachypnea 

Pain Evaluation Questions

• Character: What does the pain feel like? (for example, dull, pinching, pounding, sharp, shooting, throbbing, pounding, stinging, or 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: Clinicians should ask other relevant questions based on a review of systems, following the patient's complaint.

Signs and Symptoms of Drug-Seeking Behavior and Diversion

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

Behaviors suggesting opioid drug use disorder include:

• Aggressive demand for more drugs
• Forging prescriptions
• Increased alcohol use and lack of control
• Increasing dosage 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

Assessing a patient in need of opioid analgesics requires a detailed history, a thorough physical examination, and appropriate laboratory and radiographic studies. Depending on the circumstances, consultation with psychiatrists, addiction specialists, physical therapists, and occupational therapists should be a consideration.[16]

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

Overview Of Safe Prescribing Assessment Guidelines

Healthcare professionals are trained to prescribe pain medications; however, controlled substances are commonly misused. The list below provides an overview of the requirements for the safe prescribing of controlled substances, followed by a more detailed discussion.

• History
  • Review the chief complaint
  • Obtain current and past medical conditions
  • Obtain a list of current and past medications prescribed and dosage
  • Obtain the past medical records of patients
  • 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), and tobacco; mental health (depression assessment); and relevant personal factors, such as dependents, education, employment, living situation, marital status, and legal issues
  • Review opioid abuse risk assessment
  • Review the state prescription drug program
• Physical examination
  • Conduct a head-to-toe detailed physical examination
• Laboratory screening
  • Obtain a urine drug test

Chronic Pain Assessment

Standard blood work and imaging are not indicated for chronic pain; however, clinicians can order them when specific causes of pain are suspected. These investigations should be considered 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] The most common comorbid conditions related to chronic pain include major depressive disorder and generalized anxiety disorder. 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, patients with depression often complain of fatigue, sleep changes, loss of appetite, and decreased physical activity. These symptoms can make their pain worse over time. Importantly, patients with chronic pain are at an increased risk for suicide and suicidal ideation.[20][21]

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

Addiction Risk Assessment

Clinicians should consider information from the patient's history and physical examination, input from 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] Based on this assessment, patients can be stratified into 3 risk categories:

• Low risk: These patients require standard monitoring, vigilance, and care. Characteristics include:
  • Objective signs and symptoms with localizable physical pathology
  • Confirmatory testing, such as physical examination findings, computed tomography (CT), and magnetic resonance imaging (MRI)
  • No individual or family history of substance abuse
  • At most, mild medical or psychological comorbidities
  • Age younger than 45
  • High pain tolerance
  • Active coping strategies
  • Willingness to participate in multimodal therapy
  • Attempting to function at normal levels

• Moderate risk: These patients require an additional level of monitoring and more frequent contact with their healthcare provider. Common characteristics include:
  • Significant pain
  • Defined pathology with objective signs and symptoms
  • Confirmatory testing, such as physical examination findings, CT, and MRI
  • Moderate psychological problems controlled by therapy
  • Moderate comorbidities are well-controlled by medical treatment 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 3 regions of the body
  • Moderate levels of pain acceptance
  • Active coping strategies
  • Willing to participate in multimodal therapy
  • Attempting to function at normal levels

• High risk: These patients require intensive and structured monitoring, frequent follow-up contact, consultation with an addiction psychiatrist, and limited monthly prescription of short-acting opioids. Key characteristics include:
  • Significant, widespread pain
  • No objective signs and symptoms
  • Pain involves more than 3 body regions
  • Divergent drug-related behavior
  • Individual or family history of addiction, dependency, diversion, hyperalgesia, substance abuse, or tolerance
  • Major psychological problems
  • Age older than 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, a detailed history of the patient should be obtained, including:

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

When considering opioids, clinicians must 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, consultation with a psychiatrist or addiction specialist is recommended. If current substance abuse, withhold prescribing until the patient is involved in an addiction treatment and monitoring program.

Assessment Tools

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.[25] Commonly used tools include:

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

CAGE, CAGE-AID, and CAGE-Opioid: The CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consists of 4 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: The Current Opioid Misuse Measure is a 17-item patient self-reported assessment designed to identify abuse in patients with chronic pain. It identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy.

Diagnosis, Intractability, Risk, and Efficacy 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 5-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 5-item assessment to evaluate for aberrant drug-related behavior. The tool 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, psychological disorders, and other risk factors.

Pain Assessment and Documentation Tool: Guidelines from the CDC, the Federation of State Medical Boards, and the Joint Commission emphasize the importance of documentation from both a quality and medicolegal perspective. The Pain Assessment and Documentation Tool was developed to help clinicians accurately document relevant information.

Screener and Opioid Assessment for Patients with Pain-Revised: The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a screening tool that addresses the history of alcohol or substance use, cravings, mood, psychological status, and stress. The SOAPP-R helps assess the risk level of aberrant drug-related behaviors and determine the required level of monitoring.

VIGIL

• Verification: Is the patient a responsible user of opioids?
• 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

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.

A study suggests that monitoring frequency should be based on the patient's risk level (see Table. Recommended Monitoring Frequency Based on Risk Levels).[27] 

Table 1. Recommended Monitoring Frequency Based on Risk Levels

Abbreviation: UDT, Urine drug test.

Testing is typically performed using class-specific immunoassay drug panels; however, this may be followed by gas chromatography/mass spectrometry for the detection of specific metabolites. The test should identify the specific drug. If urine test results suggest aberrant opioid use, the issue should be discussed using a positive, supportive approach, and the discussion should be documented.

Treatment / Management

Opioid analgesics should be prescribed for a limited duration, typically ranging from several days to 3 to 4 weeks. Patients need education on the risks and benefits of opioid treatment. Treatment goals should be established at the outset, including the estimated period, expected adverse effects, expected pain improvement, and the importance of not exceeding the prescribed dose without prior consultation with a healthcare provider. The treatment plan should include the selected drug, the starting dosage, measures to track pain relief, and any associated therapies, such as occupational or physical therapy.[28]

The initial patient dose should always be the lowest dose possible, and, if necessary, the dose and frequency can be gradually increased to achieve the desired effect. Dosing should be adjusted to achieve efficacy and tolerability. Patients should clearly understand the need for regular monitoring of progress and the importance of frequently assessing the benefits and risks. Patients should be aware of complications such as constipation, fatigue, nausea, and the risk of respiratory depression. Patients should make sure that only one prescriber prescribes and monitors opioid analgesic therapy. Furthermore, 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- versus 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, opioid prescriptions should include a treatment agreement or written informed consent for any treatment for more than a few days. Treatment agreements should include the following:

• Substance use disorder and misuse risks
• Drug interactions
• Physical dependence
• Motor impairment
• Short- and long-term risks/benefits
• Adverse effects, such as 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 require patients to limit opioid prescriptions to a single clinician and consent to random urine drug screenings. Patients should be instructed to contact their prescriber with any concerns and to schedule in-person appointments for medication refills. The agreement should discuss monitoring, the need for follow-up visits, proper storage, and safe disposal of unused opioids. The agreement should list potential reasons for the discontinuation of opioid therapy.

Overview Of Safe Treatment With or Without Controlled Substances

Healthcare providers generally should consider using a noncontrolled substance to alleviate pain. However, if this fails, and the decision is made to prescribe a controlled substance, 2 important documents should be obtained before beginning therapy:

• Informed consent: This document should include the prescribed drug; risks, such as overdose, respiratory depression, dependence, drug interaction, death, and, in females, the risk of neonatal withdrawal syndrome; benefits, such as pain relief; desired goal or outcome; expected length; and follow-up care. These goals should be collaborative.

• Patient-provider agreement: This agreement is signed by the patient and provider, outlining the responsibilities of both parties, the goals of controlled substance use, and the consequences of nonadherence to the treatment plan.
  • The first prescription is a trial with a determined follow-up appointment
  • Includes tablet counts if needed
  • Refills and how they are handled
  • Use of a single healthcare provider for all controlled substances
  • Exit strategy when goals are achieved

Mild pain: Treatment is typically initiated with acetaminophen or a nonsteroidal anti-inflammatory drug, or in some cases, both. Whenever possible, alternative pain relief therapies, including physical therapy, massage, electrotherapy stimulation, yoga, biofeedback, and acupuncture, should be considered.

Moderate pain: A mild opioid such as codeine or tramadol should be started. In addition, supplemental alternative pain relief therapies should also be considered.

Severe pain: A more potent opioid such as hydrocodone, hydromorphone, oxycodone, or morphine is generally used. Immediate-release controlled substances with a half-life of 2 to 4 hours are used until the dose is stabilized. Dosage adjustments are made every 2 to 3 days. Extended-release or long-acting opioids with a half-life of 8 to 12 hours in the same family are added later. Additionally, supplemental alternative pain relief therapies are considered.

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. Pharmacological and nonpharmacological approaches should be evaluated. Patients with moderate-to-severe chronic pain who have been assessed and treated with nonopioid 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, discontinuation, risk assessment, and managing opioid use harm.

Pain Referral

Referral to a pain management specialist is recommended for patients with debilitating pain that is unresponsive to initial treatment. The pain may occur in multiple locations, requiring multimodal treatment, increased dosages for adequate pain control, or invasive procedures to control pain. Treatment for both pain and a comorbid psychiatric disorder has been shown to significantly reduce both pain and symptoms of the psychiatric disorder.[29] Pain may also worsen concurrent depression; thus, the treatment of pain has been shown to enhance responses to depression treatments..[30] There are multiple pharmacological, adjunct, nonpharmacological, and interventional treatments for chronic, severe, and persistent pain. (B2)

Pharmacological Options

The list of pharmacological options for chronic pain is extensive. This list includes nonopioid analgesics such as nonsteroidal anti-inflammatory drugs, acetaminophen, and aspirin. Medications such as tramadol, opioids, and antiepileptic drugs (gabapentin or pregabalin) can be useful. Furthermore, other possible pharmacological therapies include antidepressants, such as tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors; topical analgesics; muscle relaxers; N-methyl-D-aspartate receptor antagonists; and alpha-2 adrenergic agonists. 

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

Major Types of Pain and Their Treatment Options

Musculoskeletal pain: Chronic musculoskeletal pain is nociceptive in nature. Treatment follows a stepwise approach that includes a combination of nonopioid analgesics, opioids, and nonpharmacological therapies. First-line treatment includes acetaminophen or nonsteroidal anti-inflammatory drugs, both of which are effective for osteoarthritis and chronic back pain.[32][33][34] However, nonsteroidal anti-inflammatory drugs are relatively contraindicated in patients with a history of heart disease or myocardial infarction, renal disease, or those on anticoagulation or with a history of ulcers.[35][36] There is limited evidence supporting the superiority of one nonsteroidal anti-inflammatory drug over another. One nonsteroidal anti-inflammatory pharmacological agent may have a limited effect on a patient's pain, whereas 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 nonsteroidal anti-inflammatory drugs may warrant consideration of opioid analgesics. (A1)

Opioids are considered a second-line option; however, they may be warranted for managing pain in 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 be initiated with extreme caution in patients with chronic musculoskeletal pain.[40] Opioids commonly cause significant adverse effects, including opioid-induced hyperalgesia, constipation, dependence, and sedation. For chronic musculoskeletal pain, opioids are not superior to nonopioid analgesics.[41][42](A1)

Opioid analgesics should be reserved for cases 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. Patients must make an informed decision after a thorough discussion of the risks, benefits, and available alternatives to opioid therapy.[41][43][44] Patients taking opioids greater than 100 morphine milligram equivalents per day are at significantly increased risk of adverse effects. Adverse effects of opioids, such as respiratory compromise, 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 that severely impairs quality of life.[47](A1)

There is an estimated 78% risk of an adverse reaction to opioids, such as constipation or nausea, and a 7.5% risk of severe adverse reactions, including immunosuppression and 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 is 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 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 pain: First-line treatment for neuropathic pain often includes gabapentin or pregabalin, which are calcium channel alpha-2-delta ligands. These agents are indicated for postherpetic neuralgia, diabetic neuropathy, and mixed neuropathy.[52] There is limited evidence supporting the use of other antiepileptic medications for treating chronic pain. Many of these medications, such as lamotrigine, are associated with a more significant adverse effect profile. However, carbamazepine stands out as an exception; it is effective in treating trigeminal neuralgia and other types of chronic neuropathic pain.[53][54](A1)

Alternatively, antidepressants such as serotonin-norepinephrine reuptake inhibitors or tricyclic antidepressants are an option. Antidepressants are beneficial in treating neuropathic pain, central pain syndromes, and chronic musculoskeletal pain. In neuropathic pain, antidepressants have shown a 50% reduction in pain, which is considered significant compared to the average 30% reduction observed with other pain treatments.[55][56](A1)

The serotonin-norepinephrine reuptake inhibitor duloxetine is effective in treating chronic pain, osteoarthritis, and fibromyalgia.[57] Furthermore, the efficacy of duloxetine in treating comorbid depression is comparable to other antidepressants.[58][55] Venlafaxine is also effective in treating neuropathic pain.[59] Additionally, tricyclic antidepressants, such as nortriptyline, can be used. However, tricyclic antidepressants may require 6 to 8 weeks to achieve their desired effect.[38](A1)

Adjunctive topical agents such as topical lidocaine are useful in treating neuropathic pain and allodynia, particularly in postherpetic neuralgia.[60][61] Topical nonsteroidal anti-inflammatory drugs, such as a strain, have been shown to improve acute musculoskeletal pain but are less effective in chronic pain. However, they are more effective than controls in treating pain related to knee osteoarthritis.[62][63] Additionally, topical capsaicin cream is an option for chronic neuropathic or musculoskeletal pain unresponsive to other treatments.[64] Botulinum toxin has also demonstrated effectiveness in treating postherpetic neuralgia.[65] The use of cannabis is also an area of interest in pain research. There is some evidence supporting the effectiveness of medical marijuana in treating neuropathic pain; however, evidence for its use in other types of chronic pain remains limited.[66](A1)

Additional Nonpharmacological 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 transcutaneous electrical nerve stimulation (TENS) units. Interventional techniques can also be used to treat chronic pain. Some of the procedures and techniques commonly used to manage chronic pain include spinal cord stimulation, epidural steroid injections, radiofrequency nerve ablations, botulinum toxin injections, nerve blocks, trigger point injections, and intrathecal pain pumps. The efficacy of TENS units has been variable, and the results of TENS units for chronic pain management are inconclusive.[67] Deep brain stimulation may be considered for post-stroke pain, facial pain, and severe, intractable pain that has not responded to other treatments.[68] There is limited evidence supporting interventional approaches to pain control. For refractory pain, implantable intrathecal delivery systems are an option for patients who have exhausted all other options. Cognitive behavioral therapy is beneficial for pelvic pain syndromes.[69] (A1)

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

Addendum

Neurology care teams prescribe opioid analgesics for chronic pain conditions, such as low back pain, migraine, multiple sclerosis, peripheral neuropathy, and traumatic brain injury. The American Academy of Neurology supports electronic prescribing of controlled substances and state prescription monitoring systems to improve patient safety in opioid analgesic prescribing.[76]

Fentanyl carries the highest risk of causing respiratory depression and reduced cerebral blood flow, which can be significantly worsened when combined with heroin (diamorphine). Due to this risk, safer opioid analgesics, such as buprenorphine, morphine, or hydromorphone, should be considered as first-line options. Oxycodone has more abuse potential compared to buprenorphine and morphine.[77](B3)

In palliative care, opioid analgesics are prescribed for cancer-related pain; however, they can cause adverse drug reactions, such as respiratory depression. Opioid analgesics were found to be incorrectly prescribed, which increased patient morbidity and mortality. There is a need for improved education and training among palliative care teams to ensure appropriate dosing for effective pain control.[78]

Smallwood et al conducted a systematic review and meta-analysis on the use of opioids for symptom palliation in patients with serious respiratory disease. Opioids have been shown to improve exertional breathlessness in exercise laboratory research studies; however, they did not improve patient breathlessness, cough, or health-related quality of life when measured at home. The risks of adverse drug reactions, such as constipation, drowsiness, and nausea/vomiting, outweigh any potential benefits to the patient.[79](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 syndrome
• 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 syndrome
• Neoplasia of the spinal cord
• Neoplastic brachial plexopathy
• Neoplastic lumbosacral plexopathy
• Osteoarthritis
• Osteoporosis
• Ovarian remnant 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 duration, typically ranging from several days to 3 to 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 adverse effects, expected pain improvement, and avoidance of using more medication than prescribed without prior discussion with a healthcare 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, typically less than 30 days. Treatment goals should be established before the initiation of opioid therapy, including 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 as needed. Healthcare providers should adhere to the following guidelines:

• Initiate treatment with the lowest effective dose and titrate based on clinical response
• Start with short-acting opioid formulations
• Discuss the need for frequent risk/benefit assessments
• Be trained to recognize the signs and symptoms of respiratory depression
• Reassess risks and benefits with each dose increase
• Decisions to titrate dose to 90 mg or more morphine equivalent dose should be justified
• Stay informed about federal and state opioid prescribing regulations
• Understand 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 the opioid dose whenever possible

Consent and Treatment

Patients must provide informed consent to the course of therapy and understand all implications of their treatment regimen.[9]

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

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

Prescribing policies should be clearly described, including details 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, conduct follow-up visits, and manage scheduled refills.

Reasons for changing or discontinuing opioid therapy should be stated. 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, adverse 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 CNS depressants, such as ethanol, diazepam, and phenobarbital.[80]

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

Anxiety

Benzodiazepines are Schedule IV medications and include drugs such as alprazolam, clonazepam, diazepam, estazolam, and triazolam. These medications are used to treat anxiety, stress reactions, muscle spasms, and sleep disorders. Benzodiazepines 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. These medications should not be discontinued abruptly, as sudden withdrawal can lead to serious or potentially life-threatening symptoms, including seizures. Benzodiazepine overdose is treated with flumazenil, a benzodiazepine antagonist administered intravenously for rapid reversal.

For the treatment of anxiety, safer alternatives such as buspirone may be considered. Buspirone acts on serotonin and dopamine D2 receptors, produces minimal sedation, and carries a lower risk of abuse.

Sleep

Prescribers should prioritize non-benzodiazepine sleep medications such as eszopiclone, zolpidem, and zaleplon whenever possible. These medications act on gamma-aminobutyric acid type A receptors in the brain but typically have fewer adverse effects and a lower risk of dependence, placing them in Schedule IV. Other alternatives include melatonin and ramelteon.

Stimulants

Commonly abused stimulants include dextroamphetamine, methamphetamine, and methylphenidate. These drugs work by enhancing the effects of neurotransmitters such as norepinephrine and dopamine in the brain. Although stimulants increase alertness, cognition, energy, and motivation, they also induce vascular constriction, resulting in elevated heart rate and blood pressure, increased respiratory rate, dilated airways, elevated blood glucose, and insomnia. Stimulants 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. These drugs are classified as Schedule II substances.

Modafinil is a slightly safer alternative. This drug works by blocking the reuptake of dopamine and other neurotransmitters. Modafinil is classified as a Schedule IV drug due to its somewhat safer profile.

The American Society of Interventional Pain Physicians guidelines recommend 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 change in dosage or drug, the frequency of patient visits should be increased. Chronic response to opioids should be monitored by evaluating the 5 A's.

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

Signs and symptoms, if present, that suggest 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-engagement in life
• Lack of hygiene

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

Acute Overdose Management

Accidental or deliberate overdose is always a risk factor in patients taking opioids. Patients and their families should be educated on the signs and symptoms of an overdose and basic emergency management until the arrival of paramedics.[81]

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 permit the distribution of naloxone 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.

Although opioid antagonists such as naloxone, naltrexone, and nalmefene are available, acute overdoses are typically 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.

Opioid overdoses decrease when patients have access to naloxone. Clinicians should also prescribe naloxone to high-risk patients who are prescribed opioids. A managed care pharmacy health plan noticed that not all opioid high-risk patients were prescribed naloxone. Patients who were prescribed greater than 90 morphine milligram equivalents were also deemed to have been prescribed naloxone to reduce the risk of overdose.[82]

Prognosis

Clinicians 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. 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 30% reduction in pain can significantly improve a patient's function and quality of life.[83] However, the long-term prognosis for patients with chronic pain shows reduced function and quality of life. Improved outcomes in patients with chronic pain are achievable, particularly with the effective treatment of comorbid psychiatric conditions. 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 of suicide compared to the general population.

Spinal cord stimulation results in inadequate pain relief in about 50% of patients. Tolerance can also occur in up to 20% to 40% of patients. The effectiveness of spinal cord stimulation decreases over time.[84] 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. With timely and appropriate treatment of acute and subacute pain, the progression to chronic pain may be prevented, thereby minimizing its impact on the patient's 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 is linked to a 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, adverse effects, and possible complications.

Acetaminophen is a standard pharmacological therapy for patients with chronic pain, either as a single agent or in combination with an opioid analgesic. Hepatotoxicity occurs with doses exceeding 5 g/d [85] and is the most common cause of acute liver failure in the United States.[86] Furthermore, hepatotoxicity can occur at therapeutic doses for patients with chronic liver disease.[87]

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.[88] These agents should be used with caution in older patients with painful diabetic neuropathy. Additionally, gabapentin or pregabalin, combined with opioid analgesics, has been shown to increase the rate of patient mortality.[89]

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

Feared complications of opioid therapy include addiction and 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.[90] The long-term risks and adverse effects of opioids include constipation; tolerance; dependence; nausea; dyspepsia; arrhythmias, particularly QTc prolongation with methadone; and opioid-induced endocrine dysfunction, which can result in amenorrhea, impotence, gynecomastia, and decreased energy and libido. Additionally, there is a dose-dependent risk of opioid overdose with increasing daily milligram morphine equivalents.

Complication rates for spinal cord stimulators are high, ranging from 5% to 40%.[91][92] Lead migration is the most common complication, resulting in inadequate pain relief and necessitating revision and anchoring.[93][94] Lead movement often occurs in the cervical region of the spinal cord, given an increased range of motion of the cervical vertebrae.[95][96] Spinal cord stimulator lead fracture can occur in up to 9% of placements.[97][98] Seromas are also very common and may require surgical incision and drainage.[99][91] The risk of infection following a spinal cord stimulator placement is between 2.5% and 12%.[100][101] Finally, direct trauma to the spinal cord can occur. Among potential complications, a spinal cord abscess is the most significant infectious complication. A dural puncture can cause a post-dural headache in up to 70% of patients.[102][103][99] A spinal epidural hematoma is the most significant adverse event associated with spinal cord stimulator placement. This condition requires immediate neurosurgical decompression of the hematoma. The incidence of a spinal epidural hematoma is 0.71%.[104]

Drug Diversion and Drug Seeking

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, or stolen from clinics, hospitals, or pharmacies.[24]

Common drug-seeking behaviors may include:

• Aggressive demands for more opioids
• Asking for opioids by name
• Demonstrating behaviors indicative of opioid use disorder
• Forged prescriptions
• Increased alcohol use
• Increasing medication dose without the healthcare provider's 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 healthcare 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, the following actions should be considered:

• 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, it violates the treatment agreement. In such cases, healthcare providers may decide to discharge patients from their practice. However, if the relationship is terminated, the healthcare provider must do so legally. Healthcare providers should avoid abandoning patients, which means ending a relationship without considering the continuity of care and without providing proper notice to patients. To avoid abandonment charges, patients must be given proper advance notice to allow them to secure another clinician 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 DEA. The activity should be documented and reported to law enforcement if drug diversion has occurred.