Opioid Uses For Chronic Pain

Chronic pain can be described as pain persisting more than 90 days, or three months. Generally speaking, the pain lasts far longer than expected. Descriptions of chronic pain vary and can be mild to severe, short-lived to long-lived, or an annoyance to debilitating. Approximately 100 million people in the United States have chronic pain. Half of those, or 50 million, people experience pain daily. Furthermore, the pain is so severe that it corresponds to a pain scale score greater than or equal to seven out of ten.

Acute pain is an alert put out by the body telling us we are injured or ill. We seek help whether it is in an emergency room, urgent care clinic, or at our primary care doctor’s office. In contrast, chronic pain is the never-ending communication of pain to the nervous system. Untreated pain has the tendency to amplify over time, which causes even more pain. The amplification of untreated pain is a result of the brain’s increased sensitivity to the continuous transmission of pain stimuli.

risks of opioid useChronic pain can be correlated with lower socioeconomic status (SES) and appears to be more common in this cross-section of society. Perhaps it can be partially explained by barriers encountered when trying to access health care, an all too common occurrence among the indigent. Chronic pain also correlates with psychiatric disorders like anxiety and major depressive disorder (MDD). The evolution of hypertension also correlates with chronic pain. Other chronic pain correlates include anger, stress, and lassitude (fatigue).

The treatment of chronic pain should take advantage of various modalities, which may include consultations with pain specialists, medications, procedures, and imaging studies. Medications, the most efficacious avenue, are the cornerstone of any chronic pain management program. Medications target mediators of inflammation, as well as blockade pain receptors in the nervous system.  The most effective class of drugs targeting the mechanisms mentioned are opioid analgesics.

Opioid analgesics are strong blockers of painful stimuli, whether acute or chronic. They are not used without peril or adverse effects, however. Opioid medications are subject to rampant abuse and risks of death. Although these are concerns, correct and responsible use of opioid agents can provide extraordinary analgesia (pain relief) and may improve bodily function. The remainder of this discussion focuses on the management of chronic pain with long-term prescription of opioids, including methods, benefits, and hazards.

Chronic lower back pain is one of the most common conditions treated with long-term opioid therapy. The majority of the population, estimated at 80%, in the United States has experienced at least one episode of back pain in their lifetime. Five percent of these people grapple with chronic lower back pain. The lumbar and sacral divisions of the spinal column, or back, are commonly affected by chronic pain. Common causes for chronic lower back pain are strains, sprains, infection, and trauma; although most people battling chronic back pain cannot pinpoint any specific triggers. Prevalent etiologies of chronic lower back pain are as follows:

Vertebral disk disorders such as DDD, bulging discs, and ruptured discs can be the cause of chronic lower back pain. Age-associated spinal changes play a significant role in the development of DDD. Bulging, also called protruding, discs occur due to the anterior shifting of the central gel-like material found in discs. In contrast, ruptured, also called herniated, discs occur as a result of herniation of the central gel-like material in discs causing massive inflammation and pain. The conditions mentioned irritate the spinal nerves, which carry information to and from the brain and spinal cord, exiting in the vicinity of the discs. The irritation damages the nerves of the spine leading to acute back pain, which has the potential to become chronic and debilitating.

Another cause of lower back pain that can become chronic is vertebral compression fractures. The fractures occur when bone in the vertebral column collapses onto itself. Osteoporosis, which causes bone to become thin and weak, is the main cause of compression fractures. Osteoporosis predominates in postmenopausal women, but men can also be diagnosed with it. Clinically, vertebral compression fractures can lead to loss of adult height. Improper healing of compression fractures can lead to fusions of the vertebrae at multiple levels and a “dowager’s hump,” which limits the motion of the back and further adds to the pain burden.

Vertebral compression fractures are usually the result of trauma. The fractures can occur singly (split) or in many broken pieces (burst). The pain of vertebral compression fractures may be excruciating and decrease quality of life. It has been established that untreated vertebral compression fractures can be a cause of persistent pain and possibly damage the spinal cord leading to paralysis. A potential treatment for this disorder is a procedure called a kyphoplasty, which entails physicians injecting a cement-like material into the area of fracture to stabilize the bone. The stabilization of bone during a kyphoplasty can decrease the chronic lower back pain associated with compression fractures.

Spinal stenosis is another condition that can lead to chronic lower back pain. The condition is characterized by a restriction of space in the spinal canal. Causes of this condition include aging, arthritis, trauma, and spondylolithesis. Spondylolithesis is caused by spine instability resulting in one vertebra slipping forward onto another vertebra. The condition can advance to spinal stenosis, as well as be a primary source of chronic lower back pain. Both spinal stenosis and spondylolithesis can compress spinal nerves leading to inflammation and pain.

OpioidsOther etiologies of chronic lower back pain are scoliosis and ankylosing spondylitis. Scoliosis refers to abnormal curvature in the spine, which is normally straight. It affects some people mildly and others severely. Severe scoliosis usually requires surgical correction. Ankylosing spondylitis can be defined as an arthritic condition of the spine. The inflammatory condition can cause the spine to fuse and render the affected area immobile and fixed.

Chronic lower back pain treatment is multifaceted and takes advantage of prescription medication and non-medication options. Surgery is sometimes needed to treat chronic lower back pain, but there are no guarantees surgery will alleviate pain. Persistent pain despite back surgery is termed failed back surgery syndrome. This surgical outcome correlates with factors such as poor patient selection, surgical error, recurring spinal disease, and conditions imitating back pathology.

The hip, unilaterally or bilaterally, is another area that can experience chronic pain. Common causes of chronic pain in the hip include osteoarthritis, tendinitis, bursitis, and fracture. Hip fracture occurs predominantly in the elderly as a result of osteoporosis, which indicates thin and weak bone. Osteoporotic bone has a high incidence of fracture, whether in the hip or spine. Chronic hip pain can also be a consequence of osteopenia, a condition that is characterized by bone loss that is not severe as osteoporosis.

Hip arthroplasty, or surgical correction of the hip joint, is a common technique used to deal with fractures of the hip. The procedure not only helps with hip pain, but it can also be a source of chronic hip pain on its own. Another condition requiring hip arthroplasty, or hip replacement, is end stage osteoarthritis, which is inflammation of bones and joints. The associated chronic inflammation leads to deterioration of cartilage on the articular surfaces of joints. Eventually all of the cartilage in the hip joint disappears and leaves the naked surfaces of bones rubbing together, which can lead to severe pain. At this juncture, hip replacement should become a major consideration.

Chronic daily headache can also be a cause of chronic pain. Recurrent headaches are a part of life for close to 53 million people in the United States. Accordingly, headaches account for the majority of purchases of over-the-counter medications. By definition, chronic daily headache occurs >15 days per month for a period of three months or more. The disorder is not a diagnosis, but rather a descriptive phrase. Primary categories of chronic daily headache are chronic migraine, chronic tension-type, hemicrania continua, and new daily persistent. Medication overuse headaches are a secondary cause of chronic daily headache.

The most common causes of chronic daily headache are chronic tension-type headache and medication overuse headache. Chronic tension-type headaches are usually bilateral, pressure-like in nature, and are mild to moderate in intensity.

Chronic migraines are usually unilateral, pulsating in quality, and moderate to severe in intensity. Other symptoms of migraines may include nausea, vomiting, visual disturbances, sensitivity to light, and phonophobia (sensitivity to loud sounds).  Migraines may or may not have associated aura, which is most often a visual disturbance. Migraines are more often diagnosed in women and occasionally correlate with the onset of menstruation.

Hemicrania continua is a persistent unilateral headache that responds to the non-steroidal anti-inflammatory drug indomethacin (Indocin). The cause of hemicrania continua is unknown. New daily persistent headaches are usually bilateral, although they can be unilateral, and have an intensity described as mild to moderate. New persistent daily headaches can mimic chronic tension-type and chronic migraine headaches.

Cancer can also cause chronic pain. Tumors can penetrate bones and joints, leading to acute and chronic pain. Cancers can spread to other areas, a process termed metastasis, and cause chronic pain. Radiation therapy and chemotherapy for cancers can also be a source of chronic pain. These two cancer therapies not only kill cancerous cells, but also kill normal cells adjacent to the cancerous area. Lastly, chronic pain can provide clinical clues as to the location of tumors.

Other causes of persistent, chronic pain include fibromyalgia, multiple sclerosis, Crohn’s disease, post herpetic neuralgia, and neuropathy. Fibromyalgia is characterized by diffuse muscle pain, joint stiffness, and fatigue. It is often misdiagnosed or not recognized as it shares overlap with some mood disorders such as depression and anxiety. Multiple sclerosis (MS) is an immune-mediated process directed against myelin, which is the fatty substance surrounding and insulating nerves in the central nervous system. Forms of MS include relapsing-remitting (most common form), secondary-progressive, primary progressive, and progressive-relapsing.

Crohn’s disease is best described as an inflammatory bowel disease. It can occur anywhere from the mouth to the anus in the digestive tract. Post herpetic neuralgia is the most common complication of shingles, a viral disease that can cause a painful rash. Shingles is caused by the chickenpox, also known as the varicella-zoster, virus. Neuropathy is a disease of nerves that can lead to pain, numbness, and tingling in the extremities. Diabetics have a particularly high rate of developing neuropathy.

Opioids As A Treatment For Chronic Pain

Pain can tell us that we have encountered harmful or dangerous elements in our external environment. Nociception is the encoding and processing of harmful stimuli in the central nervous system.

Nociception has four stages:

  • Transduction, which refers to the process of converting external stimuli into pain signals
  • Transmission, which refers to pain signals being directed toward the spinal cord and ultimately to the brain
  • Modulation, which is the process of dampening or amplifying pain signals
  • Perception, which refers to the awareness of pain

Pain relievers, or analgesics, target different parts of the pathway to pain. Mu receptors in the spinal cord govern the ability to feel pain, or nociception. These receptors function to suppress the communication of pain signals. Opioid analgesics have an immense affinity for these receptors. It is this mechanism of action that allows opioids to provide sustained relief of pain.

Morphine was the earliest of the opioid analgesics and is still used today for the treatment of pain. Newer opioids have evolved that are quite efficacious in their treatment of moderate to severe discomfort. Examples include codeine, oxycodone, hydrocodone, and fentanyl. The usefulness of opioids is mitigated by their potential for risks and adverse side effects however.

Risks And Adverse Effects Of Opioid Use

Opioid analgesics do more than just block pain. They have adverse effects, cautions, and risks that all physicians as well as patients should know. Adverse side effects of opioids may include fatigue, constipation, sedation, nausea, vomiting, confusion, dry mouth, constricted pupils (miosis), and itching (pruritis). More serious adverse effects may include urinary retention, respiratory depression, hallucination, hypothermia, delirium, hyperalgesia (increased sensitivity to pain), and abnormal heartbeats (arrhythmias). Large doses of opioids can lead to serious respiratory depression, oxygen deprivation, unconsciousness, and death.

Other less known side effects of chronic opioid administration include:

  • Immunosuppression: Opioids can lead to a diminished immune response on behalf of B-lymphocytes, also known as B-cells. B-lymphocytes are responsible for the manufacture of antibodies, which help us fight infections.
  • Amenorrhea: Opioids can cause hormonal disturbances that culminate in the absence of the female menstrual cycle.
  • Galactorrhea: Opioids can cause inappropriate secretion of milk from the breasts.
  • Decreased libido: Libido can also be referred to as sex drive.
  • Testosterone suppression: Data has shown a direct correlation between chronic opioid therapy and hypogonadism, which is a reduction or absence of the male sex hormone testosterone. Testosterone is responsible for the development and maintenance of secondary male sexual characteristics. Symptoms of the disorder may include a decrease in muscle mass, impaired growth of body hair, micropenis, gynecomastia (breast tissue development), erectile dysfunction (ED), decrease in bone mass, and infertility.

The following situations are absolute contraindications to the initiation of long-term opioid therapy:

  • Severe respiratory disease or instability
  • Uncontrolled suicide risk or acute psychiatric instability
  • Substance use disorders not in remission and not being actively treated
  • Allergy to opioid agents
  • Co-administration of drugs capable of inducing life-limiting or threatening drug to drug interactions
  • Active diversion of opioid agents
  • Prior adequate trials of opioids that were discontinued due to intolerance, serious adverse effects, or lack of efficacy

Chronic opioid therapy should be initiated with caution in the following situations:

  • Ongoing treatment of a substance use disorder
  • Patients with the following conditions—untreated obstructive sleep apnea, central sleep apnea, chronic pulmonary disease, paralytic ileus of the bowel, and history of respiratory depression in an unmonitored setting
  • High risk for suicide or unstable psychiatric disorder
  • Complicated pain such as headaches not responsive to other pain treatment
  • Conditions that could negatively affect medication compliance such as cognitive impairment, unwillingness to take medication, unwillingness to abstain from at-risk activities
  • Social instability
  • Mental health disorders

Opioid analgesics should be taken with care. They should not be administered in combination with antihistamines, sleep aids, alcohol, muscle relaxants, or some antidepressants. Caution should also be exercised when prescribing opioids to the elderly. If prescribed to the elderly, opioids should be used in the lowest possible dose that gives adequate pain relief. The elderly are at higher risk for confusion, respiratory depression, and delirium than other patient populations.

The lowest possible dose of opioid that gives reasonable analgesia should be prescribed to patients with decreased renal function or failure. This population is at high risk for the accumulation of toxic metabolites called glucoronides in the blood, which are toxic to the kidneys. Patients that operate heavy machinery or drive vehicles should be prescribed opioids with caution due to their increased risk of drowsiness, sedation, and slowed reaction times.

Long-term prescription of opioids can lead to tolerance, dependence, and addiction. Tolerance is an adaptation characterized by the need for increasing or more frequent dosing of an opioid. Tolerance may occur to both the pain relieving effects of opioids and to some of the unwanted side effects such as respiratory depression, nausea, and sedation. Dependence can be physical or psychological.

Physical dependence is a scenario in which the abrupt cessation of an opioid, rapid tapering of an opioid, or administration of an opioid antagonist results in a withdrawal syndrome. Initial symptoms of withdrawal syndrome may include depression, irritability, anxiety, cravings, yawning, runny nose, and excessive sweating. One day after discontinuation of the opioid, withdrawal symptoms may progress to goose bumps, myalgia (muscle pain), loss of appetite (anorexia), muscle twitching, fluctuating body temperature, hypertension, abdominal cramping, and elevated heart rate (tachycardia). Over the next three days withdrawal symptoms may include severe diarrhea, weight loss, unceasing vomiting, and insomnia. Physical dependence on opioid analgesics is an expected outcome in all individuals who undergo long-term opioid therapy.

Psychological dependence is an emotional need for a substance that has no underlying physical need. In some respects, psychological dependence is harder to overcome than physical dependence. Psychological dependence correlates include physical abuse, post-traumatic stress disorder, low socioeconomic class, sexual abuse, and partial relief of pain. Abuse and misuse can arise from partial pain relief. Abuse is the harmful usage of a medication or drug. Misuse is any deviation from the accepted medical use of a medication or drug.

Addiction is characterized by a persistent pattern of dysfunctional opioid analgesic use that may include any or all of the following:

  • Loss of control over the use of opioids
  • Preoccupation with obtaining opioids, despite adequate pain relief
  • Continued use despite adverse physical, psychological, or social consequences

It is important to note that the terms tolerance and physical dependence do not imply addiction. Patients with a prior history of substance abuse have the highest incidence of problems with prescription opioids. Furthermore, behaviors such as prescription forging or tampering are considered maladaptive. These behaviors have been noted to be common among those addicted to prescription opioid medication. Concerned medical professionals should confront patients about the possibility of addiction and refer them to appropriate programs such as counseling and drug rehabilitation.

Types Of Opioid Medications

pain pillsOpioids remain one of the most popular treatments for pain, whether short or long lived. Opioids relieve pain rated moderate to severe, which helps patients reclaim mobility, function, and quality of life. Opioid analgesics can be given in varied fashions including pills, intravenous, injections, liquids, transdermal patches, and lozenges. The U.S. Food and Drug Administration (FDA) lists all opioids as schedule 2 drugs, which means they have high abuse potential.

Morphine is one of the oldest and most commonly administered opioid analgesics. Various delivery methods are utilized with injection being the most popular. It has a great affinity for the mu receptors located in the brain and spinal cord, which allows it to provide superior analgesia. When injected, morphine’s bioavailability approaches 100%; but when given orally, its bioavailability drops to 50%. The opioid is particularly useful when administered for post-surgical pain, low back pain, and hip pain. In controlled studies, steady and modest doses of morphine showed superior efficacy in the treatment of chronic pain.

Codeine was discovered in 1832 and still makes the World Health Organization’s list of the most important medications needed in a basic health system. Codeine is used for pain rated mild to moderate. It is most commonly mixed with acetaminophen in an oral formulation known as Tylenol #3. Codeine is also mixed with promethazine, a medication to fight nausea, to treat and manage cough associated with many ailments. The mixture is increasingly used in popular culture as a drug of recreation mixed with lemon-lime soda and is called “syrup,” “lean,” or “purple drank.” Overdose, disability, and death as a result of codeine abuse and addiction are becoming increasingly common.

Hydrocodone is an opioid agent obtained from codeine. Its most common use is in the treatment and management of pain rated moderate to severe. The opioid is particularly useful in pain secondary to a diagnosis of cancer. Like codeine, hydrocodone can be mixed with acetaminophen in oral formulations with the brand names Vicodin, Norco, and Lortab. It is considered stronger than codeine with respect to pain relief. Hydrocodone is the most commonly written prescription for opioids in the United States.

Oxycodone is another opioid agent used to treat moderate to severe pain. Like the other opioids, it has an extraordinary affinity for the mu receptors in the central nervous system. Like hydrocodone, it can be mixed with acetaminophen in an oral formulation with the brand name Percocet. Oxycodone is also available as a single ingredient medication in immediate release and controlled release forms prescribed under the brand names Roxicodone and OxyContin. The most common route of oxycodone administration is orally. It provides pain relief for causes of chronic pain such as cancer, neuropathy, neuralgia (nerve pain), phantom limb syndrome, hip osteoarthritis, and Crohn’s disease.

Oxycodone serves double duty in the case of Crohn’s disease, an inflammatory bowel disease, providing relief from pain and associated diarrhea. Oxycodone, especially the controlled released form OxyContin, has a high potential for abuse and addiction. As a drug of recreation, OxyContin is abused and misused via crushing and snorting. Crushing the controlled-released form causes the immediate release of the medication when ingested, which increases the potential for adverse effects. Recent efforts by pharmaceutical manufacturers have produced a tamper-resistant formulation of OxyContin, which stymies some abusers.

Fentanyl was first synthesized in 1960. It has been measured to be 80 to 100 times more potent than morphine. Fentanyl can be administered by injection or intravenously. It is utilized as anesthesia for surgery and for severe pain before, during, and after surgery. Fentanyl can also be prescribed as a transdermal patch, with the brand name Duragesic, for long-term opioid therapy. In its patch form, fentanyl is a good choice in the treatment of pain due to neuropathy (nerve disease), osteoarthritis, and back disorders.

An intrathecal pump, also known as a spinal drug delivery system, can be used to administer fentanyl into the intrathecal space of the spine. It involves implanting a small pump or using a catheter to deliver fentanyl directly to the spinal cord. Spinal delivery of fentanyl is efficacious in the treatment and management of back pain and pain caused by cancer. After programming, patients can self-administer the opioid. To prevent misuse and abuse, there is a lockout mechanism to prevent the patient from using too much fentanyl within a specified period of time. Like other opioids, fentanyl has high abuse potential and recreational use and overdose deaths are increasing.

Managing Opioid Use

Starting long-term opioid therapy for pain should not be undertaken haphazardly. Unfortunately, the inadequate treatment and management of chronic pain is all too commonplace. The norm is unacceptable as approximately one-third of the population in the United States suffers from chronic pain. Prior to initiation of chronic opioid therapy, the prescribing physician should exhaust all conservative measures for the treatment of chronic pain and deem them ineffective. Conservative treatment measures may include anti-inflammatory medications, anti-seizure medications, antidepressants, steroid injections, occupational therapy, and physical therapy if appropriate. As a general rule, prescription opioids are not first-line medications for treating chronic pain.

Long-term opioid therapy for pain should be comprehensive and patient-driven. The following are examples of some tenets observed in the management of long-term opioid therapy:

  1. Diagnosis. An etiology for the chronic pain should be established using appropriate testing methods.
  2. Psychological assessment for mental disorders and risks of addiction. It is not uncommon for depression to coexist with chronic pain.
  3. Informed consent. Medical providers should discuss the risks and potential adverse effects of long-term opioid therapy.
  4. Narcotic contract. A treatment agreement usually stating the patient agrees to obtain narcotic prescriptions through a primary provider, fill narcotic prescriptions through a primary pharmacy, take only the prescribed amount of medication, consent for random urine drug testing, and refrain from the use of illicit drugs or alcohol in combination with the prescribed opioid.
  5. Assessment of pain level and function, pre- and post-intervention. It is important to support continued long-term opioid therapy with improvement in function.
  6. Appropriate trial of opioid with or without adjunctive medications. Those adjunctive medications may include anti-inflammatory drugs, antidepressants, and muscle relaxants.
  7. Reassessment of pain score and level of function at each and every appointment. It can be used for the continuation or adjustment of opioid therapy.
  8. Routine and regular assessment of analgesia, adverse effects, activity, and aberrant behaviors. These are known as the “4 As” of pain management.
  9. Periodically review the pain diagnosis and other conditions. Diagnostic procedures may have to be repeated for improving or worsening of pain symptoms.
  10. Documentation. It is necessary to protect not only the clinician, but the patient too. It can also reduce malpractice claims and risk of regulatory sanction.

Long-term opioid therapy should take advantage of the following assessment and screening tools:

  • Roland Morris Disability Scale
  • Brief Pain Inventory
  • 9-Item Patient Health Questionnaire (PHQ-9)
  • Screener and Opioid Assessment for Patients with Pain (SOAPP)
  • Opioid Risk Tool (OPT)

Prescribers should employ a 12-item checklist prior to initiating chronic opioid therapy. The 12-item checklist should cover the following areas:

  1. A pain assessment (0-10 scale)
  2. Clear documentation of the reason for opioid administration
  3. Clear documentation of benefits gained by opioid administration
  4. Establishment and review of goals for chronic opioid administration
  5. Current medication list
  6. Documentation of the patient’s social history and substance abuse potential
  7. Physical examination to delineate area(s) of pain
  8. Documentation of potential risks and benefits of long-term opioid therapy
  9. Referral for additional evaluation and treatment, if needed
  10. Updated Pharmacy Board review
  11. Random urine drug testing on a monthly basis
  12. A narcotic contract signed by the patient within the last six months

Dosing and its frequency are important issues in long-term opioid therapy. In controlled, randomized studies, reliable dosing of opioid analgesics controlled pain and improved mood and quality of life. If adequate control of pain cannot be established, providers should consider the addition of adjunctive therapy or intermittently rotating classes of opioids. Chronic pain patients should be encouraged to report increased pain or the development of new pain.

Physicians who treat chronic pain with long-term opioid therapy should be well-versed in the treatment of serious adverse effects and overdoses. Overdose with respect to opioids can be managed with opioid blockers. These opioid antagonists work by competing with opioids for access to opioid receptors. By blocking access of opioids to their receptors, this class of drug reverses the ill effects associated with overdose. Opioid antagonists can also be utilized in the treatment of withdrawal syndromes. Opioid receptor blockers include medications such as naloxone, buprenorphine, and the dual drug naloxone combined with buprenorphine.


opioid use mental healthApproximately 100 million people in the United States have been diagnosed with chronic pain, and daily pain affects 50 million chronic pain sufferers. It can lead to insomnia, mood disorders, and severe disability. The treatment of chronic pain is multifaceted and incorporates pharmaceutical and non-pharmaceutical modalities. Opioids are a wildly popular choice utilized in the treatment and management of chronic pain. However, their use is not without perils and side effects.

Chronic pain occurs with the greatest frequency in areas of the body such as the hips, low back, knees, shoulder, ankles, and head. Common conditions leading to chronic pain are cancer, neuropathy, post herpetic neuralgia, vertebral compression fractures and Crohn’s disease. Activation of mu receptors by opioids blocks pain signals bombarding the brain and spinal cord. Illustrations of opioid analgesics are morphine, hydrocodone, oxycodone, and fentanyl. Side effects of opioid use vary, and are sometimes fatal. Risks encountered with chronic opioid therapy include tolerance, dependence, and addiction. Regardless of risks and side effects, opioids remain one of the most widely prescribed classes of medication worldwide.

Prescription of chronic opioid therapy is not for the faint of heart. Physicians should follow tenets and checklists to ensure compliance. The U.S. Drug Enforcement Agency also publishes guidelines on this subject of long-term opioid therapy. In closing, patient education can illuminate the pitfalls of chronic opioid therapy, increase responsibility and compliance, and decrease risks such as tolerance, dependence, and addiction.


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