Opioid Use for Chronic Pain
Opioids for chronic pain explained by Denver, Golden, Aurora, Boulder, Broomfield, Jefferson, and Littleton Colorado’s top pain doctors
Chronic pain can occur in regular, protracted episodes, persistently or consistently. It is often linked with time-frames of up to three months (or more). The duration and nature of pain can be termed “chronic” based on the associated condition or syndrome. A definition that does not depend on condition may be of pain that lasts beyond the expectations of normal recovery from an illness or injury. Chronic pain may be at a consistent background level or present at a greater intensity at regular intervals that begin at the same approximate time every day. Some reports estimate that approximately 9.5 million people in the U.S. experience this type of pain. Estimates also suggest that 50% of these people have pain daily, and/or suffer severe pain (i.e. if asked to rate their pain using a range of one to ten, they would assign a value of seven or higher to it).
Reduced socioeconomic status is strongly linked to chronic pain, intimating that income restrictions prevent many people with chronic pain cases from seeking medical attention and treatment. Neglecting a case is associated with further exacerbation of this type of pain, however. Chronic pain can progress over time to a point at which normal function and movement is significantly affected. For example, prolonged chronic pain may result in the inability of a patient to rise or move for a considerable length of time. Chronic pain may be a risk factor for some psychiatric disorders, including depressive disorder. It may be experienced in many areas of the body, which is influenced by the condition, injury, or disorder responsible.
Chronic pain may be treated by a range of options that work by inhibiting the associated neural activity in reaching the brain. The most conventional and possibly efficacious of these may be a course of drug therapy. Pain (including chronic pain) is associated with inflammation in the tissues affected, which some drugs can also inhibit. Other classes of drug act by binding to the pain-regulating receptors located throughout the body. These compounds are called analgesics, a drug type that has seen a wide range of developments and new products over the last 100 years.
A classic subtype of analgesic is the group of chemical analogs called opioids. Opioids have a long history of use as painkillers, sedatives, and drugs of abuse, and are highly effective in all of these. It is possible to use them for appropriate time periods in medical circumstances however. Patients can use them for pain relief, and they may also be associated with regaining function and quality-of-life improvements. Here we will focus on the uses of opioids in the treatment of chronic pain, which includes positive and the potential for negative aspects of their use. Opioids are still in widespread use, often for cases of severe, intractable chronic pain.
A condition that is often associated with opioid use is consistent and/or recurrent pain in the back. This is often subdivided based on the regions of the spine (i.e. cervical, thoracic, and lumbar) and pain in the lumbar region tends towards higher prevalence. This is influenced by many factors, including illness, injury, or muscle damage. Chronic lower back pain may also be caused directly, i.e. by damage to the bones of the lumbar spine or to spinal nerves in this region. Vertebrae (spinal bones) also contain discs that are present to support, protect, and maintain spinal integrity. “Bulging” (herniation) or other damage to these is also strongly linked to chronic lumbar pain.
Vertebral fracture is another condition associated with chronic lower back pain. They are divided into two main types. One is compression fracture, alternatively termed collapsed vertebrae. Vertebral collapse is often associated with diseases that cause bone degeneration, including osteoporosis. These conditions cause a loss of bone density that increases the risk of fractures (including vertebral fractures) over time. This is strongly linked to advanced age. The other type of vertebral fracture—a vertebral body fracture—is associated with injury or accidents, such as road traffic incidents, falls or water-diving from a height, firearm-related injuries, and so on. The prevalence of this tends to be highest in 15 to 24 year old men and seniors (i.e. those of 55 years of age or more). Vertebral body fractures are divided into two main types. Split-types are single breaks in or throughout the body of a spinal bone. Burst-types are a number of very small fractures that result in the appearance of a shattering or explosion in the vertebra. The risk of vertebral body fracture is also increased by osteoporosis. Vertebral body fractures may result in spinal cord damage that may cause motor or sensory deficits, in addition to chronic pain, if left untreated.
Chronic back pain is also associated with stenosis of the spine. This is a condition in which the spinal cord or spinal nerves are pinched or impinged upon, as a result of scar tissue accumulating within vertebrae. It may also be caused by the abnormal growth of spinal bones. These often require removal by surgery, but if this is not absolutely necessary, the normal procedure is to manage stenosis-related pain with drugs such as opioids or other minimally-invasive treatments.
Failed back surgery syndrome is chronic pain resulting from errors by surgeons in the course of procedures on the lower back. This is often due to accidental damage to nerves or other tissues in the area operated on. Patients of failed back surgeries, which are often carried out to address another source of pain, may require analgesic medication to block the associated pain for a prolonged period of time after surgery and normal recovery, which can span several months to several years. Chronic pain in the lower back can also be associated with autoimmune or inherent conditions such as arthritis or fibromyalgia.
Pain felt in the hips or legs may also be chronic. This can be associated with a wide range of variables, including joint disorders, inflammation, and injury. A very prevalent source of chronic pain in the hip joint is fracture, or damage to one or more of the bones. This condition is strongly associated with patients in their late 50s and onwards. Osteoporosis is a leading risk factor of this, which may or may not be accompanied by an accident. Hip fractures are also seen in the very young, which is associated with damage from accidents that may occur in the course of general activity, and also (possibly) with childhood obesity. Hip arthroplasty, which comes in many forms of either replacement or augmentation of damaged areas of the joint with medical hardware, is a common surgical procedure to address a fracture. Chronic pain may be a consequence of this and it is most usually treated by courses of analgesics, rehabilitative therapies, or both. Suffering from osteoarthritis can increase the probability of needing arthroscopy at some point. This is an autoimmune disorder, in which inflammatory molecules attack the joint that can result in chronic hip pain. Osteoarthritis is popularly associated with people of 55 years or more, but some research indicates that the rate of development in younger patients is on the rise.
Headache is another very common type of chronic pain. Many cases of chronic headache are a symptom of episodic (or recurrent) disorders that produce moderate to severe pain regularly at roughly the same times. It is estimated that nearly one-sixth of all people in the U.S. may have these disorders.Primary headaches are associated with direct damage to the tissues adjacent to the brain, including the facial muscles, facial and cranial nerves, skull membranes, mucous membranes, blood vessels, sinuses, ears, eyes, and subcutaneous tissue. They are not associated with brain damage, with the exception of serious secondary headaches. Tissue damage causing headaches is linked to diseases or disorders, injury, or inflammation. Some research suggests that some chronic headaches (tension-type headaches) are caused by damage to muscles, nervous tissue, or vertebrae or in the neck. Some may also be attributed to hyperactivity in the pain-perceiving regions in the brains of patients. This is rationalized by observations of patients’ constant perception of any nervous input from the face or skull as harmful, whether it is or not. Further basis for this theory may be some reports of increased pain sensitivity of tension headache patients, compared to normal healthy controls, and results indicating abnormalities in their brain tissue that regulates pain signals.
Migraines are a highly prevalent type of chronic headache disorder. Estimates suggest that migraine is the most common primary headache condition. The volume of newly reported migraine cases per year is reported to be equivalent to over a tenth of the U.S. population. Women are at a risk of approximately 3 times higher of developing a migraine condition at any point in their lives compared to men. Migraine is a recurrent condition that can form a pattern linked to the menstrual cycle of patients affected. Migraine headache episodes are often described as regular attacks of throbbing, intense pain of the head or face. Migraines are unilateral, i.e. felt on one side of the head, above or behind the eye. The pain may become bilateral, or be felt further around the same side of the face over time, particularly if not adequately treated. Other symptoms of migraine can include nausea, vomiting, neurological events, and strong adverse reactions to odors. The duration of a migraine episode can be some hours, or even a day or more.
Cluster-type headaches are similar to migraine in that they are usually felt around one eye, but also possibly in the temple on the same side of the head. They are often experienced as a series of pain episodes, of as many as eight across one day. They are associated with sleep disturbances, as they tend to have an onset while the patient sleeps, with enough intensity to induce waking. One cluster headache episode may last for 30 to 180 minutes. Cluster headaches are strongly associated with men between 20 and 40 years of age. Estimates suggest that this disorder affects 0.01% of the total global population.
Tension-type headaches are another primary headache disorder that often becomes chronic. They are typically defined as “bands” of crushing pressure around the skull or forehead. They may also be characterized as grinding, stabbing, or throbbing pains felt in major facial muscle groups. Other possible symptoms are sonophobia and photophobia. Tension headaches are associated with timeframes of about 30 minutes to a number of days. A case of tension-type headaches may be diagnosed as chronic if this pain occurs on 15 or more days every month. Tension headaches are the most common headache type, affecting approximately 210 million people worldwide. Headaches are strongly associated with demand for over-the counter medications and with medical consults resulting in prescription for stronger analgesics.
Chronic pain can also be experienced in many other body parts and regions of the body. The testicles may be a source of chronic pain. This may be associated with infection or inflammation. Consistent or recurrent foot pain of the foot may be related to factors such as structural abnormalities of the toes or heels or mechanical damage related to ill-fitting or high-heeled shoes. Chronic facial pain is linked to damage of certain major cranial nerves, or of groupings of nerve endings (ganglia) within the skull, that are responsible for facial or mandibular control. Other types of chronic pain include Crohn’s disease (an autoimmune disorder of the gastrointestinal tract that can cause pain of the extremities), postherpetic neuralgia (severe and often semi-permanent nerve damage as a result of a herpes zoster infection), and diabetic neuropathy (nervous tissue damage linked to diabetes).
Cancer may also be a source of chronic pain. Persistent back or hip pain can be linked to a concomitant cancer, as can secondary headaches. Metastatic tumors can invade bones or joints, resulting in chronic pain, as do some osteolytic cancers. Therapies that act to destroy tumors, such as chemotherapy or radiotherapy, can also cause chronic pain, as they can also result in damage to normal surrounding tissues. This type of chronic pain may last months or even years after treatment has ended. Cancer patients may require prolonged periods of pharmacotherapy, even in remission. Unexplained chronic pain may indicate a tumor pressing on nerves or other tissues in the affected areas, in some cases.
Opioids As A Treatment For Chronic Pain
Pain is the body’s natural reaction to dangerous and harmful stimuli that may threaten internal or external tissues. This information is perceived as nociception (pain) when transmitted by nerves to the brain. Nerves all over the body initially convey their signals, including pain, to the spinal cord that sends them to the areas of the brain that control pain processing. Specialized regions of many nerves (“pain fibers”) are responsible for transmitting noxious stimuli to a part of the spinal cord called the dorsal horn. The nerve cells of this region then convey this onward to the brain. These are partially controlled by large numbers of mu receptors (biological sensors). If they are activated, they can stop the dorsal horn cells sending pain signals any further.
Opioids are strongly associated with this type of receptor. They can significantly activate these mu receptors, and thus result in a large-scale delay of the pain signal transmission. This is due to their chemical similarity to endorphins and/or enkephalins, molecules naturally produced in the body to bind dorsal horn receptors (or their analogs elsewhere in the body) and regulate pain perception. Some opioids, such as heroin and morphine, can also produce a euphoric or sedative effect and, as a result, have long been the target of overuse and abuse. Additional types of opioid have been discovered or developed for use in analgesia and anesthesia. Examples of these are codeine, oxycodone, and fentanyl.
Risks And Adverse Effects Of Opioid Use
Opioid activity at the relevant receptors can have effects beyond this, however. These can include drowsiness, lethargy, numbness, and possible hallucination. Other negative side-effects include skin reactions, dry mouth, nausea, vomiting, constipation, hypothermia, and delirium. Opioid use can result in life-threatening reactions, such as cardiac problems (i.e. tachycardia or bradycardia) or respiratory depression. The latter is also a common indication of overdose, as is asphyxia. Lesser known side-effects include immune system dysfunction. For example, some reports indicate that morphine is associated with decreases in the efficiency of B-cell function. Opioids may also increase the risk or rate of renal failure. This is due to the exacerbation of their breakdown products in the body (glucuronides) of existing kidney damage. Opioids also cause a characteristic pupil-shrinking effect (miosis).
Opioids are also popularly linked to high risks of addiction, dependence, and tolerance. Tolerance is the progressive decrease in the expected response to a constant drug dose. Humans develop tolerance to opioids at a greater rate than that of any other class of drugs. There is no definitive theory of this phenomenon. Proposed reasons include changes in the numbers of receptors present or the activity of existing receptors, in response to opioid binding. Genetic and environmental factors are also implicated. There is also a genetic predisposition to unusually low opioid tolerance. Some types, particularly morphine, can easily produce life-threatening side effects if taken by an individual affected by this. Opioid tolerance is associated with increased intake by patients, which increases the risk of negative side effects and opioid dependence. Opioid dependence can be a serious problem for patients on this medication. Dependence is defined as adverse reactions to drug unavailability, such as the exacerbation of the symptoms treated, e.g. pain. Psychological and physiological types of dependence may result from opioid tolerance. Opioid dependence is associated with increased pain levels in patients in the event of discontinuation.
Physiological dependence is also associated with withdrawal; a battery of adverse reactions in response to discontinuation or decreased dose. Opioid withdrawal may be unpleasant and somewhat detrimental. Other drugs, including alcohol, are associated with more severe withdrawal, however. Opioid withdrawal often occurs in stages, the first of which is often associated with irritability, anxiety, mild depression, and autonomic effects, such as sweating and opioid cravings. These may persist into the second stage, in which the patient may also exhibit other autonomic responses such as compulsive yawning, a runny nose or eyes, and more negative mood or psychological symptoms. After the first approximate 24 hours into withdrawal, other symptoms such as feeling hot or cold, muscle spasms, goose bumps, dilated pupils, aching, and loss of appetite may also be present. The next stage may include nausea, insomnia, tachycardia, restlessness, intestinal cramping, and restless leg syndrome. Vomiting, diarrhea, and decreases in bodyweight may occur in the last stages of withdrawal. When opioid withdrawal is complete, some symptoms such as gastrointestinal disorders, hypertension, and increased pain sensitivity may still be seen. Patient education on the probability and nature of withdrawal before opioid therapy is viewed as increasingly important by authorities and prescribing physicians.
Psychological dependence is an emotional dependence on drugs such as opioids in order to cope with psychological conditions or stressors. The risk of this type of dependence is influenced by pre-existing factors, such as having experienced physical or sexual abuse. There may also be a socioeconomic component of psychological dependence. Some research also suggests some genetic factors may affect an individual’s susceptibility to opioid dependence. Psychological dependence is a contributing factor to opioid addiction. On the other hand, recent studies indicate that the rate of addiction in chronic pain patients may be lower than previously thought. A study published in 2013 concluded that just 1.9% of patients included had problems related to addiction. Other articles suggest that addiction may be associated with a patient’s perception that their chronic pain is not being treated effectively by the therapy prescribed. This may result in overuse or illicit supplementation of their prescriptions. Drug supplementation is often done with other types of opioids or drugs of other classes. This patient behavior is often termed diversion, and often comes in the form of the additional intake of benzodiazepines, etc. or of illegal forms of opioid (“illicit diversion”).
These are not the only risks linked to opioid intake. Other adverse effects include decreases in motor control and alertness, which most often occurs when taking high doses. This may affect the ability of patients to safely attempt some activities, such as driving, although some studies suggest that patients on long-term courses of opioids can perform these without issue, due to tolerance. Patients on very high doses may need to be monitored, however, due to serious side effects such as bradycardia. Patients of greater age or those with pre-existing conditions, such as lung disorders, require particularly careful monitoring. Recent studies have highlighted another possible risk. This concerns possible decreases in testosterone, leading to male hypogonadism particularly in long-term, high-dose users. However, good overall health and normal tolerance levels act to regulate the incidence of negative side effects in many patients.
Opioids remain a common form of pain treatment nonetheless. In addition, they can improve functional status and life quality for patients in whom pain may have significant effects in these areas. These drugs have a wide variety of applications and administration methods, chosen based on patient condition, the opioid type in question, and the severity of pain. Morphine, the commonest form of opioid in the history of medicine, is typically administered through a needle or catheter. It is also available as a quick-release lozenge. Morphine is often regarded as the best opioid option, as it binds and activates its receptors with a very high degree of efficacy and affinity. Its bioavailability is nearly total when administered directly, though morphine in lozenge form only achieves about 50% of this.
Morphine is often linked to high rates of tolerance, physical and psychological dependence, and abuse though some studies suggest that these may be less than previously thought. However, others indicate that addicts have a higher preference for heroin, another form of morphine, than for other opioids. Tolerance to morphine tends to develop quickly, although responses to its secondary effects such as euphoria decrease before those to its analgesic properties. Morphine tolerance is thought to play a major role in the establishment of dependence and addiction, although some researchers have demonstrated the interaction of other major risk factors, such as a history of abuse with addiction rates. Morphine intake maintained at a safe and appropriate level is associated with effective chronic pain management without abuse or overuse. Morphine administration is a conventional practice in treating hip pain, post-operative pain, and lower back pain that is not responsive to other options. This opioid may also be prescribed in short-acting applications, for significantly debilitating, intractable headache.
Oxycodone is a comparatively modern form of opioid medicine. This form also activates mu receptors. Parenteral and oral administration routes are associated with oxycodone. It plays a valuable role in treating neuropathic chronic pain, pain associated with neuralgia and cancer, pain in amputated limbs, chronic hip pain, and Crohn’s disease. Oxycodone for Crohn’s may also have the benefit of treating the often-concomitant diarrhea seen in this disorder. Oxycodone is also associated with increases in quality of life and depressive symptoms in these patients. It is also available in combination with other drugs such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs). Oxycodone is also accompanied by anticonvulsants (e.g. gabapentin), which may have a potentiating effect. It is associated with less serious negative effects than morphine, although the withdrawal symptoms are regarded as being more severe. Oxycontin®, a slow-release formulation, has been popularly linked to a high abuse potential. Due to this, it is currently being redesigned to avoid this association.
Hydrocodone is chemically similar to oxycodone. It is the opioid (in an oral formulation with acetaminophen) with the highest prescription rate in the United States. Hydrocodone is most effective in treating pain associated with cancer. It is linked to high rates of abuse, which may be an association skewed by its common availability, but some researchers believe it is has less of a link to abuse than oxycodone.
Fentanyl is a relatively new opioid, synthesized in 1960. Its potency is a hundred times greater than that of morphine. Fentanyl is applied analgesia during and after surgical procedures and to chronic pain treatment. It is available in transdermal patches, which are devices that distribute drugs into subcutaneous fat that allows a slow, long-term release. Fentanyl is also available as a lozenge attached to a stick (a “fentanyl lollipop”). This may seem frivolous, but is in fact an ingenious invention that allows slow release at the patient’s discretion, in response to pain-killing needs. These are available for chronic arthritis pain, back pain, and neuropathic pain. Fentanyl is also administered via intrathecal pump. Pumps are connected to catheters inserted into the epidural space of the spine. The pump contains a fentanyl reservoir, which the patient may activate with a hand-held controller. This method is associated with effective treatment of back pain and cancer-related pain. The negative side effects of fentanyl are largely the same as for many opioids (see above). In addition, they may also extend to severe anxiety, moderate to severe stomach discomfort, headache, hypoventilation, and anorexia. Fentanyl may be associated with a magnified risk of respiratory depression in patients with low opioid tolerance. Abuse among chronic pain sufferers who take it is largely unknown, but it is associated with increasing misuse in the general population.
Managing Opioid Use
Recommendations of opioids for chronic pain by healthcare professionals should not be given lightly. Prescription is increasingly associated with thorough assessments of patients and their suitability for opioid administration. Before prescribing opioids, the physician should confirm the failure of all non-opioid drug options available. This can be done with the analysis of data such as appropriate pain scale results and patient reports. Patient screening for abuse risk factors may be necessary.
If the patient is regarded as not at significant risk of addiction and/or dependence after this testing, opioids may be prescribed. It is recommended that intake monitoring is enacted, particularly if the dose necessary is high. Documentation can facilitate this vigilance. Recording of pharmacy and prescription paperwork is part of this. In addition, patient data, such as changes in pain rating scores, patient’s quality of life, emotional state, functional status, and any adverse effects gathered at each consultation is important. Urine testing can help to test for overuse or diversion.
An increasingly popular method of patient monitoring is a patient contract. This is an agreement, often sealed with signature, between the patient and physician that sets out rules concerning drug use, such as intake per day, a trackable prescriber or pharmacy (ideally only one) to be used, and other aspects of dose-regimen compliance. Patients on very high doses may require on-site or very close evaluation by a pain clinic or specialist. In general, physicians who prescribe these drugs should be fully aware of the risks of opioids. Patients may also need to learn about these, as it may decrease the probability of diversion, abuse, and dependence.
Techniques in analyzing the risks of opioid prescription are increasingly popular and well-regarded. These include the Opioid Risk Tool and the Screener and Opioid Assessment for Patients with Pain (SOAPP, SOAPP-R (revised) and SOAPP -SF (short form). There are also monitoring protocols and checklists available, and their validity is recognized by increasing numbers of physicians. These are often based on the DEA opioid use and administration recommendations. These may include requirements for information including:
- A patient’s pain scale results
- Assessment of the benefits of opioid treatment that other drugs have failed to provide (e.g. significant relief or functional improvement)
- History of other treatments
- Patient expectations of opioid treatment results
- Screening for risk factors
- Evidence of patient education
- Urine tests before/after prescription
- Whether a contract has been read and signed
Dose and frequency of dose should also be considered carefully by a physician before prescription. A consistent morphine dose can effectively manage pain, despite tolerance, for a significant period of time. Some research concludes stable dosing can sustain appreciable levels of pain relief and quality of life. If factors such as tolerance begin to affect these, steps such as switching to another opioid or adding an appropriate adjunct (e.g. combining the existing medication with a tricyclic antidepressant or anticonvulsant) may restore the effect. Higher doses of the existing opioid should be a last resort. Increased pain may indicate a deterioration of the condition treated or that a new one has developed. If pain increases while on a steady dose of opioids, a consultation with a physician is advised. Pain specialists and physicians should be familiar with treatments for overdose, withdrawal symptoms, and serious adverse effects such as respiratory depression. Overdose can be treated using appropriate antagonists (e.g. naloxone for morphine), which may be mu receptor blockers. These are molecules that compete with others, including opioids, to occupy receptors, but do not have pain-blocking properties.
If it becomes necessary for a patient to stop taking opioids, these antagonists are also a part of withdrawal treatments, as they can ameliorate the effects of receptor non-activation to some extent. Other examples of opioid receptor antagonists include buprenorphine and naltrexone. Buprenorphine is a partial antagonist, but also a partial agonist which means it can have some of the receptor activity of both heroin and naloxone. It is an effective withdrawal treatment and some trials have demonstrated its treatment of chronic lumbar pain. Transdermal patches of buprenorphine are now available for this and achieve decreases in pain severity and improvements in normal function.
Chronic pain affects nearly ten million people in the U.S., with 50% of these experiencing severe pains daily. This condition may result in the significant functional or motor impairments of patients. Chronic pain can arise in many areas of the body. Many of these forms are managed by drug therapy. Opioids are a class of drugs among the most effective and common in relief from chronic pain. They are also linked to a high incidence of negative side-effects and abuse, unfortunately.
Opioids take effect by activating receptors for endorphins, enkephalins, and other naturally-occurring analgesics, which significantly inhibit the conduction of pain signals to the brain. This drug class includes morphine, oxycodone , codeine, and fentanyl. Opioids also have unwanted side-effects, including nausea, vomiting, drowsiness, lethargy, constipation, hypothermia, delirium, dry mouth, and skin reactions. Overdose can cause respiratory failure, if not prevented using adequate procedures in time. Opioids can also affect the immune system. They may also accelerate renal failure if taken by kidney damage patients. They are linked to a high index of tolerance, dependence, and abuse. Tolerance is the progressive decrease in response to the effect of a consistent dose-regimen. Dependence can result in a discomfiting series of withdrawal symptoms.
Recent research has found opioid addiction or abuse may not be strongly associated with the chronic pain patients taking them. Patient abuse or addiction may rather be linked with dissatisfaction with the extent of their treatment. This may be associated with an increased tendency to overuse prescribed opioids or to supplement them with additional drugs (diversion). The risk of adverse effects and abuse is reduced by a good level of health and a lack of risk factors, found in the majority of patients. Opioids can achieve significant pain relief and improvements in functional status for patients that may have been bed-ridden previous to taking them. Opioid administration varies based on opioid type, pain severity, and patient condition.
A thorough assessment should be done when considering the prescription of opioids. The physician should ensure that all other drug options are ineffective, for example. Risk factor screening (i.e. for low tolerance and abuse potential) is also required. Compliance checklists contain requirements for information including medical and drug intake history, whether a patient compliance contract has been signed, and a definitive need for opioids based on pain severity and intransigence. Patient education about responsible opioid intake, including the risks of withdrawal and addiction, and the benefits of avoiding these, may play a vital role in maintaining the efficiency of opioid therapy in consistent and safe chronic pain management.
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