Under treatment of chronic pain remains a persistent problem, with an estimate of approximately 30% of those who suffer from chronic pain receiving less than adequate treatment.5 Pain medication decreases (modulate) pain by altering transmission at various points of the pain pathways.3
Analgesic agents are often given orally as this is convenient and allows a relatively steady blood concentration of the drug. Pain medication may be administered on an as-needed basis for episodic pain, or it may be given routinely for chronic pain. The use of routine, around-the-clock medication sustains a steady state in the blood and offers better pain relief for those with persistent pain. When deciding on what medication to use, side effects must be taken into consideration.
Classes of medications include non-opioid analgesic agents, antidepressants, muscle relaxants, antiepileptic medications, topical agents and opioids. Some get effective relief from one medication, but some get better pain relief from a combination of medications that work on different pathways. Unfortunately, research is sparse on combination medication in the management of pain.
Considering all co-morbidities is an important step in the management of pain. When a patient is afflicted with chronic pain and depression, some medications may help effectively manage both conditions (for example, duloxetine is approved to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain in addition to depression). It is also important to establish the pathophysiology of the pain syndrome, evaluate the medication list, and consider the side effects of the medications being prescribed.
The clinician should distinguish between neuropathic pain and nociceptive pain. The etiology of neuropathic pain must be established and if the etiology is reversible, manage the underlying problem. For example, if a medication (e. g., metronidazole, nitrofurantoin, isoniazid, or many cancer agents) is the etiology of the neuropathy – stop that medication.
Medications used in the treatment of neuropathic pain include calcium channel alpha 2-delta ligands (gabapentin and pregabalin), tricyclic antidepressants, serotonin-norepinephrine uptake inhibitors (SNRIs), the lidocaine patch and narcotic analgesics.
Nociceptive pain is typically treated with non-narcotic and opioid analgesia. Common causes of nociceptive pain include arthritis and chronic low back pain. Acetaminophen is often used as a first-line agent in the management of nociceptive pain.
Acetaminophen has become the chief cause of acute liver failure. According to government statistics, there are close to 30,000 hospital admissions annually associated with acetaminophen overdose. Patients must be warned that alcohol and acetaminophen is a particularly dangerous mixture, and alcohol consumption needs to be avoided when taking this medication. In January 2011, the Federal Drug Administration (FDA) requested drug manufacturers to limit the amount of acetaminophen in combined products to 325 milligrams per dose. The FDA also required that labels carry a ‘black-box’ warning highlighting the fact that acetaminophen can result in severe liver damage.5
Acetaminophen is not an anti-inflammatory agent but is a very common over the counter medication used for the management of pain. Acetaminophen is commonly administered with opioid medications to reduce the amount of opioid medication needed to manage the pain. There is some evidence of renal toxicity with long-term use of high-dose acetaminophen over the years.
Acetaminophen is dosed 325 to 650 mg every four hours or 500-1000 mg every 6 hours, not to exceed 3000 to 4000 mg a day. In the pediatric population, acetaminophen is dosed at 10-15 mg/kg/dose every 4-6 hours with a maximum of 75 mg/kg/day, but no more than 4000 mg a day. The dose should be reduced in those with hepatic insufficiency or alcohol abuse. Absolute contraindication to acetaminophen is liver failure while relative contraindications include chronic alcohol abuse or hepatic insufficiency. Those who are on a statin cholesterol medication may need a lower dose of acetaminophen.
Before going to a stronger pain medication, it is important that clinicians determine that acetaminophen is given in the proper dose. The use of up to 1000 mg per dose (in adults) may be necessary to provide relief.
NSAIDs are used as alternative options to acetaminophen and are indicated for mild to moderate pain, while some are indicated for severe pain. Like acetaminophen, they act synergistically with opioids. Because they act as an anti-inflammatory agent, they are often used for arthritis, strains, sprains, bursitis and tendonitis. The most frequently used NSAIDs are acetylsalicylic acid (Aspirin), ibuprofen (Advil, Motrin), naproxen (Aleve) and diclofenac (Voltaren). NSAIDs are believed to work by inhibiting the production of the enzymes cyclooxygenase 2 (COX-2) and (COX-1) that are involved in the synthesis of prostaglandins that mediate inflammatory responses and also cause pain. COX-1 is involved in the protection of the stomach lining, and one of the most frequently cited side effects of NSAIDs is stomach bleeding.3
NSAIDs are associated with more side effects and are potentially more problematic, especially in older adults. In older adults, the American Geriatric Society guidelines recommend that persistent pain due to osteoarthritis not be primarily managed with non-steroidal anti-inflammatory agents. The use of topical NSAIDs is a good option for those with localized pain.
Absolute contraindications to NSAIDs include an active peptic ulcer, chronic kidney disease or heart failure. Relative contraindications include a history of peptic ulcer disease, Helicobacter pylori infection, hypertension, or concomitant use of selective serotonin receptor inhibitors or corticosteroids.
Other side effects of NSAIDs include renal insults, adverse cardiovascular effects, headaches, constipation and mental status changes. Gastrointestinal effects may include gastric ulceration and dyspepsia. Taking the medication with food or antacids may reduce the risk of dyspepsia. Those at high risk of gastric ulceration – older age, on corticosteroids, bleeding problems, or a history of gastric ulceration – should likely not use NSAIDs. The use of a proton pump inhibitor reduces the risk of gastric ulceration with the use of NSAIDs. NSAIDs have the potential to interact with many antihypertensive medications, aspirin, selective serotonin reuptake inhibitors, corticosteroids and warfarin.
NSAIDs have the potential to cause nephrotoxicity. NSAIDs inhibit prostaglandin synthesis which leads to vasoconstriction of the afferent arteriole in the kidney, resulting in a reduction in the glomerular filtration rate. NSAIDs should be used cautiously in those with renal impairment.
NSAIDs have the potential to lead to cardiovascular complications and have been implicated in increasing the risk of myocardial infarctions, especially in patients who take high doses over a prolonged period of time. For those with high cardiovascular risk, the use of NSAIDs should be limited.
They should also be avoided in those with thrombocytopenia (low platelet count). Patients receiving warfarin or heparin should not receive NSAIDs. NSAIDs have been shown to impede thrombocyte aggregation, which can increase the risk of bleeding.3
Antidepressant use in Pain Management
Antidepressant medications are effective for multiple types of chronic pain. They have shown effectiveness in neuropathic pain, fibromyalgia and pain associated with depression. This next section will look at some of the antidepressants used in the management of pain.
Tricyclic antidepressants (TCA) modify pain by inhibiting the uptake of norepinephrine and serotonin and block multiple channels including the sodium, adrenergic, cholinergic and histaminergic channels. Medications in this class include nortriptyline, desipramine, amitriptyline and imipramine.
Nortriptyline and desipramine (secondary amine tricyclic antidepressants) are preferred agents in this class as they are associated with a better side effect profile. These agents are often used in the management of neuropathic pain, but can also be used in chronic pain management as adjuvant agents.
Tricyclic antidepressants need to be used cautiously in older adults as they have many side effects (constipation, dry mouth, mental status changes, blurred vision, urinary retention, blood pressure change, tachycardia, and heart block). They should be used very cautiously or not at all in those with cardiac or electrocardiographic abnormalities. The analgesic effect is typically noticed in a shorter period of time and at a lower dose than when treating for depression. Some patients will have a diminishing of side effects as their body adapts to the medications.
In adults, most TCAs are often started at 10 mg per day and is then titrated up to 75 mg per day. Older individuals rarely tolerate doses more than 75-100 mg per day. It may take up to 8 weeks before analgesia is appreciated, but pain relief may be noticed as soon as one week.
Serotonin-norepinephrine reuptake inhibitors are used for neuropathic pain but can be used for other types of pain. Duloxetine (Cymbalta) is indicated for diabetic neuropathy and painful chronic musculoskeletal conditions such as osteoarthritis and chronic low back pain. It is also approved for fibromyalgia. Common side effects include insomnia, drowsiness, dry mouth, fatigue, nausea and dizziness.
It should not be used in those with severe renal insufficiency or hepatic insufficiency. When stopped, it should be tapered slowly due to withdrawal symptoms.
Venlafaxine (Effexor), another SNRI, is sometimes used for neuropathic pain, but it is an unlabeled use. Venlafaxine may lead to increased blood pressure. When the medications stopped, it should be tapered slowly to minimize withdrawal symptoms.
Gabapentin is approved in adults for post-herpetic neuralgia up to 3600 mg per day in divided doses. Dosage adjustment is needed in those with renal disease. It comes in an extended release form called Gralise. Gabapentin is often used off-label for other neuropathic conditions including diabetic neuropathy, generalized neuropathic pain, anxiety, and post-operative pain.
Pregabalin (Lyrica) can be used in adults for fibromyalgia, neuropathic pain (diabetes related), neuropathic pain in those with spinal cord injury and post-herpetic neuralgia. Both Pregabalin and duloxetine have been given regulatory approval for pain management in neuropathic diabetic pain in the United States, Canada and Europe.19
Topical lidocaine is used as first-line therapy for post-herpetic neuralgia. It must be applied to intact skin, and up to three patches may be applied for no more than 12 hours in a 24-hour period.
Muscle relaxants can be used in the management of acute and chronic pain. Cyclobenzaprine (Flexeril) was initially classified as a tricyclic antidepressant but was then remade as a muscle relaxer. Side effects are similar between the TCAs and the cyclobenzaprine including sedation, dry mouth, constipation, urinary retention and mental status changes.
Carisoprodol (Soma) is another commonly used muscle relaxer that has been increasingly linked to dependence. Due to the concerns of dependence, this medication is less commonly used. The most common side effect of all muscle relaxers is sedation.
In recent times, opioids therapy has become more commonly used; in the past, it was only used for severe acute pain and cancer pain. Approximately 8 million Americans with chronic pain are being treated with opioids.5 A recent position paper from the American Academy of Neurology suggested that there is evidence for good short-term pain relief with opioids, but no good evidence exists for continuation of pain relief or improved function for extended periods of time without sustaining serious risk of dependence, overdose, or addiction.20 Opioids function by activating opioid receptors that are located in the spinal cord and brain. The majority of the pain relief related to opioids is as a result of their actions on the cells in the PAG and the descending pain pathways.
Opioid medications are associated with multiple side effects including constipation, nausea, vomiting, pruritus, abdominal cramping, sedation, and mental status changes. Multiple interventions are available to reduce side effects.
Constipation is a frequent issue in those who use opioids. Risk factors for constipation include older age, those with intra-abdominal pathology and those who eat a low-fiber diet. Those on opiates should be encouraged to increase fiber intake, drink plenty of fluids and be encouraged to exercise. Stool softeners (e.g., docusate sodium) and stimulants (e.g., bisacodyl) may be needed to manage constipation. An osmotic laxative such as polyethylene glycol or lactulose may also be considered, which may be added to stools softeners/stimulants for resistant constipation.
Antiemetic medication can help treat nausea.
Antihistamines can treat pruritus.
Opioids are associated with somnolence and other mental status changes. Patients do develop tolerance to these symptoms over weeks. Reducing the dose may lessen the mental status changes. An adjunctive medication may be added to the lower dose of opioid to help manage the pain. Rarely, the use of a stimulant can be used to manage the sedation due to opioid use.
Respiratory depression may occur, but it is uncommon when the medication is used carefully. Starting low and slowly titrating the dose will reduce the risk of respiratory depression. Problems arise with rapid titration, the addition of another drug that may suppress the respiratory drive (benzodiazepine, alcohol or a barbiturate) or the patient overdoses. Sedation precedes respiratory depression, so when starting a patient on opioid therapy encourage them to take the first dose in the office to be monitored or in the presence of a responsible adult who can help monitor the patient. The level of consciousness should be assessed 30-60 minutes after the opioid is given. The next dose should be held and immediately contact the prescriber if there is a reduced level of consciousness, has hypoxia or has a respiratory rate less than 10 per minute.21 Tolerance and addiction are two serious concerns with opioid use. Tolerance refers to the fact that over a period time the amount of the drug taken must be increased to achieve the same amount of pain relief. Tolerance has become a problem with the long-term use of opioids and results from desensitization and down-regulation of opioid receptors in the body.
Addiction refers to the fact that withdrawal symptoms occur if the drug is stopped. Different opioids have different levels of risk for causing addiction, i.e. morphine, which is a naturally occurring opioid is highly addictive and produces a sense of euphoria. Synthetic opioids result in little or no feelings of euphoria and have less risk of causing addiction. Use of opioids over a prolonged period of time can have negative consequences for pain control - central sensitization caused by opioids can result in increased pain sensitivity known as hyperalgesia.3
The most serious risk linked with opioid use is overdose.5 Death from overdosing on semi-synthetic opioids occurs every 19 minutes in this country, and after car accidents, it is the second major cause of accidental deaths
While there are many opioids, morphine is considered by many as a standard comparator for other drugs. Morphine can be given orally, rectally, intravenously, subcutaneously or intramuscularly.
Morphine is used for moderate to severe acute pain and chronic serious pain. It comes in multiple formulations. For acute pain, it is dosed at 10-30 mg every 4 hours for those who are opioid naïve. It is available as tablet, solution, suppository and parenteral solution. The immediate release tablet is dosed 15-30 mg every 4 hours as needed and the oral solution is dosed 10-20 mg every 4 hours as needed. It can also be given rectally and is often dosed 10-20 mg every 4 hours as needed. Morphine also comes in a controlled release form, a sustained release form and an extended release form.
Longer-acting formulations include Avinza, Kadian, and MS Contin.
Side effects of morphine are similar to other opioid analgesics and include dry mouth, constipation, bradycardia, hypotension, nausea, drowsiness, dizziness, mental status changes, fever, itching, weakness, hypoxia and urinary retention.
Morphine should not be used in those with a hypersensitivity to morphine, those with toxin-mediated diarrheal disease, those with severe/acute asthma, paralytic ileus or severe respiratory depression. The extended release form should not be used in those with GI obstruction.
The extended release forms of morphine are not interchangeable. Changing from one medication to another should be done only by those experienced in how to do this. Extreme caution should be used when using highly concentrated solution, so overdoses do not occur.
Drug interactions commonly seen with morphine include:
- Amphetamines may increase the effect of morphine
- Anticholinergic agents may increase the side effects of morphine (constipation and urinary retention)
- Antipsychotic agents with morphine may reduce blood pressure
- Nasal azelastine (Astelin) with morphine enhances the central nervous system (CNS) depression effect
- Clopidogrel therapeutic efficacy may be reduced with morphine
- Diuretics side effects may be increased with morphine
- Hydrocodone enhances CNS depression
- Hydroxyzine enhances CNS depression
- MAO Inhibitors enhances side effects of morphine
- Selective serotonin reuptake inhibitors with morphine enhance the serotonergic effect and CNS depression
- Zolpidem enhances the CNS depression
Morphine is pregnancy category C. It does enter breast milk, and it is not recommended in those who are breastfeeding.
Fentanyl is a very strong synthetic opioid. It is 100 times more powerful than morphine and can be given as an injection, transdermal patch (Duragesic), an oral transmucosal lozenge (Actiq), a sublingual tablet (Abstral), a sublingual spray (Subsys), a buccal tablet (Fentora), a buccal film (Onsolis) and a nasal spray (Lazanda). The transdermal patch is used in opioid tolerant patients with moderate to severe pain and is often started at 25 mcg per hour and changed every 72 hours.
Fentanyl can be used for multiple reasons including premedication for surgery, for general anesthesia, as an adjunct to general and regional anesthesia, and chronic pain management. The transdermal patch is indicated for around the clock pain management in those with chronic severe pain. Fentanyl transmucosal and intranasal is indicated for cancer pain.
While no official dosage adjustment is recommended in those with renal or hepatic impairment, those with mild to moderate renal or hepatic impairment should likely have the dose reduced by 50 percent with the patch, and use is not recommended in severe renal or hepatic impairment. Transmucosal and nasal spray have no specific recommendations for dose reduction in renal or hepatic impairment.
Common side effects of fentanyl include dry mouth, edema, bradycardia, dehydration, respiratory depression, shortness of breath, diaphoresis, nausea/vomiting, constipation, application site erythema (patch), weakness, muscle rigidity, mental status changes, headache, sedation, and CNS depression.
As with most opioids, contraindications includes hypersensitivity, toxin-mediated diarrheal disease, and paralytic ileus. It should not be used for short-term pain, post-operative pain and should not be used for those who have a severe respiratory disease. The transmucosal and nasal form of fentanyl are typically only used by specialists for opioid-tolerant cancer patients.
The patch form should not be exposed to external heat as this may increase absorption of the medication. Exercising with the patch on has the potential to increase absorption of fentanyl. In addition, patients with a fever may also notice an increase in absorption of the medication. The patch should only be applied to intact skin; it contains aluminum and must be removed prior to an MRI.
Like many medications, there are multiple potential interactions. Some more common interactions include:
- Alcohol may enhance CNS depression
- Beta-agonists may decrease the serum concentration of fentanyl
- Amphetamines may enhance the effects of fentanyl
- Anticholinergic medications along with fentanyl increase the risk of urinary retention and constipation
- Antipsychotic agents may increase the risk of low blood pressure
- Azelastine nasal spray may enhance CNS depression
- Beta-blockers with fentanyl enhance bradycardia
- Calcium channel blockers may enhance hypotension or bradycardia
- Hydrocodone may enhance CNS depression
- Selective serotonin reuptake inhibitors with fentanyl may enhance serotonergic properties
- Zolpidem effects may be enhanced
Fentanyl is pregnancy category C. It does enter the breast milk and is not recommended in the breastfeeding mother.
Oxycodone is a schedule II controlled substance and is available in multiple forms.
- Immediate release (Roxicodone) is dosed 5-30 mg every 4-6 hours (lower range for opioid-naive patients). There is also an abuse deterrent tablet (Oxceta) that comes as a 5 mg and 7.5 mg tablet.
- The controlled release tablet (OxyContin) is indicated for those who require around the clock pain control. It is dosed 10 mg every 12 hours to start and titrated carefully.
Oxycodone is often combined with other analgesic agents such as acetaminophen (e.g., Percocet, Roxicet, Tylox), aspirin (e.g., Percodan, Endodan, Oxycodan) and ibuprofen (Combunox).
Those with a creatinine clearance less than 60 mL/min should have the dose adjusted down as serum concentration of oxycodone will increase in renal insufficiency. Those with hepatic impairment should have doses reduced; with the extended release formulation, the starting dose should be lowered one-third to one-half and slowly titrated up to affect.
Side effects include drowsiness, dizziness, itching, constipation, nausea and vomiting. Less common side effects include dry mouth, headache, abnormal dreaming, blood pressure changes, diaphoresis, weakness and fever.
Oxycodone is contraindicated in those with paralytic ileus, significant respiratory depression, hypercarbia, acute or severe bronchial asthma, and GI obstruction.
Caution should be used in those with biliary tract impairment such as acute pancreatitis as it may lead to constriction of the sphincter of Oddi. It may lead to an elevation of intracranial pressure (ICP) and should be used carefully in those with intracranial lesions, elevated ICP or a head injury.
Extended-release tablets may be lodged in the GI tract including the throat in those with swallowing issues. It may also lead to intestinal obstruction or diverticulitis.
Common drug interactions with oxycodone:
- Alcohol may enhance CNS depression
- Amphetamines may increase the effect of oxycodone
- Anticholinergic agents may increase the side effects of oxycodone (constipation and urinary retention)
- Antipsychotic agents with oxycodone may reduce blood pressure
- Nasal azelastine (Astelin) enhances CNS depression
- Diuretics side effects may be increased with oxycodone
- Hydrocodone enhances CNS depression
- Hydroxyzine enhances CNS depression
- MAO inhibitors enhance side effects of oxycodone
- Mirtazapine may enhance CNS depression
- Rifampin may decrease the serum concentration of oxycodone
- Selective serotonin reuptake inhibitors with oxycodone enhance the serotonergic effect and CNS depression
- Zolpidem enhances the CNS depression
Oxycodone is pregnancy category B and D if used for an extended period of time or near term. It does enter breast milk and is not recommended in those who are breastfeeding.
Hydrocodone, which was classified as a Schedule II Controlled Substance in October of 2014, is available as a combination pill with non-narcotic analgesia (e.g., Lorcet, Lortab, Norco and Vicodin) and by its self in an extended release form. The combination pill has a short acting version of hydrocodone and is dosed 2.5 to 10 mg of hydrocodone every 4-6 hours as needed for moderate to severe pain.
Hydrocodone extended-release (Zohydro ER) is typically dosed 10 mg every 12 hours in treatment-naive patients. It is used for severe pain requiring around the clock dosing of hydrocodone. The dose may be increased every 3-7 days in 10 mg increments.
Those with severe hepatic impairment should start at the lowest dose and titrate up very slowly while monitoring for side effects. Caution should be used with renal impairment as plasma concentration may rise.
Side effects include constipation, nausea, vomiting, dry mouth, drowsiness, headache, dizziness, pruritus and nausea.
Contraindications to hydrocodone include paralytic ileus, severe asthma, severe respiratory depression and hypercarbia.
- Alcohol may enhance CNS depression
- Amphetamines may increase the effect of hydrocodone
- Anticholinergic agents may increase the side effects of hydrocodone (constipation and urinary retention)
- Nasal azelastine (Astelin) enhance the CNS depression
- Diuretics side effects may be increased with hydrocodone
- MAO inhibitors enhance side effects of hydrocodone
- Selective serotonin reuptake inhibitors with hydrocodone enhance the serotonergic effect and CNS depression
- Zolpidem enhances the CNS depression
- Hydrocodone is pregnancy category C. The extended release form minimally enters the breast milk and should be used with caution in breastfeeding and the combination pill has been shown to enter breast milk and its use is not recommended.
As of August 18, 2014, the DEA placed tramadol into a Schedule IV of the Controlled Substance Act. It is indicated for moderate-to-severe pain, and the immediate release form is dosed at 50-100 mg every 4-6 hours for a maximum of 400 mg a day.
Tramadol is also indicated for chronic moderate-to-severe pain.
Tramadol also comes in an extended release form, ConZip and Ultram ER.
When prescribing tramadol to older adults, use the lower end of the dosage range and titrate slowly. In those over 75 years old, 300 mg a day should not be exceeded and utilize extreme caution with the extended release form.
In those with a creatinine clearance less than 30 mL/min, only the immediate release formulation should be used with doses of 25-100 mg split every 12 hours (maximum dose of 200 mg a day). In those with severe liver impairment, the immediate release form should be given to a maximum of 50 mg every 12 hours.
Side effects include flushing, dizziness, constipation, nausea, vomiting, dyspepsia, itching, headache, somnolence, insomnia and weakness. Less common side effects include orthostatic hypotension, mental status changes, euphoria, rash, hot flashes, diarrhea, dry mouth, anorexia, joint pain, blurred vision and sweating.
Patients may experience withdrawal symptoms from tramadol that may include nausea, diarrhea, anxiety, pain, sweating, tremor and rigors. Extended use of tramadol may lead to dependence, and these medications should be tapered slowly to reduce the risk of withdrawal symptoms.
Tramadol is contraindicated in those who are hypersensitive to the agent and those with severe liver or kidney impairment. The extended-release tablet should not be used with psychotropic drugs, opioids, hypnotics, acute intoxication with alcohol or centrally acting analgesics and the extended release capsule formulation should not be used in those with severe respiratory depression, severe asthma or hypercapnia.
Tramadol has been shown to increase the risk of seizures. This risk is increased in those who take serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, other opioids, or other drugs that lower the seizure threshold. The risk may also be increased in those who have seizures or are at risk for seizures such as those who have a CNS infection, cancer, history of head trauma or while patients are going through drug or alcohol withdrawal.
Caution should be used in those with respiratory disease as those with significant disease may be at increased risk for respiratory depression.
- Alcohol may enhance CNS depression
- Amphetamines may increase the effect of tramadol
- Anticholinergic agents may increase the side effects of tramadol (constipation and urinary retention)
- Antiemetics may reduce the effects of tramadol
- Antipsychotics and tramadol may result in reduced blood pressure, increased risk of neuroleptic malignant syndrome and increased risk of serotonin syndrome
- Nasal azelastine (Astelin) enhances CNS depression
- Carbamazepine with tramadol may enhance CNS depression; tramadol may reduce the therapeutic effect of carbamazepine
- Cyclobenzaprine and tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
- Diuretics side effects may be enhanced with tramadol
- Hydrocodone may enhance CNS depression
- Hydroxyzine may enhance CNS depression
- MAO inhibitors with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
- Metoclopramide with tramadol may increase side effects of metoclopramide or increase the risk of serotonin syndrome or neuroleptic malignant syndrome
- Selective serotonin reuptake inhibitors with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
- Tricyclic antidepressants with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
- Warfarin with tramadol may affect the anticoagulant effect
- Zolpidem enhances CNS depression
- Tramadol is pregnancy category C. It enters the breast milk and is not recommended in lactating women
Case Study 1
Ms. L is a 52-year-old female with a history of bilateral knee osteoarthritis; she currently rates the pain as a 7/10 in her right knee and 6/10 in her left knee. She takes celecoxib 200 mg twice a day and uses 1000 mg of acetaminophen for breakthrough pain about 3 times a day. She has been stable with these medications for the past 6 months, but over the last month, she has not been getting adequate relief from her pain and has been progressively disabled. She also reports having to stop exercising because of the pain in her knees.
In addition to osteoarthritis, she has a past medical history of hypertension, dyslipidemia, depression, and obesity. She has a past surgical history of an appendectomy as a child. She is currently on atorvastatin, lisinopril, celecoxib and acetaminophen. She has no known allergies.
She has no history of alcohol, drug or substance abuse. She has a strong family network including a supportive husband of 25 years and two sons who live within twenty miles of her home. She has a past history of depression but is currently not depressed.
The physical exam shows significant crepitus in both knees and obesity (BMI of 34). She is unable to fully extend the right knee due to pain.
An x-ray demonstrates moderate arthritic changes in both knees. The patient is unwilling to consider surgery of her knees.
The prescriber offers tramadol immediate-release 25 mg in the morning, which is titrated every three days in 25 mg increments as distinct doses to 100 mg/day (25 mg four times a day). Pain control was still not adequate, and the dose was then increased by 25 mg every three days to 50 mg every 6 hours.
Pain control was significantly improved, and then the patient was given tramadol SR 200 mg once a day. The patient was able to function and exercise. Her quality of life was much improved.
Oxymorphone, a schedule II medication, can be given intravenously, subcutaneously, intramuscularly or orally. Oxymorphone is pregnancy category C, and it is unclear if it is excreted in breast milk and should, therefore, be used cautiously.
Hydromorphone can be given orally, rectally, subcutaneously, intramuscularly or intravenously. Hydromorphone is pregnancy category C and is excreted in breast milk. It is not recommended for lactating women.
Methadone can be given intravenously, subcutaneously, intramuscularly or orally. Methadone is a high-risk drug to lead to overdose. It has a half-life of up to five days and may accumulate in the body. Methadone may also prolong the QT interval leading to cardiac arrhythmias especially at doses higher than 120 mg a day. Methadone should be used for severe pain that has not been responsive to other agents and only by clinicians with specific training in the use of methadone. Methadone is also used in detoxification.
Tapentadol (Nucynta, Nucynta ER) is used for acute moderate to severe pain. This medication is not recommended for those with severe liver or renal insufficiency. It is also indicated for diabetic peripheral neuropathy.
Meperidine is not recommended as a first-line agent for chronic pain as it is associated with high rates of central nervous system toxicity.
Table 3: Oral Opioid - Adult Dosing
|Drug||Initial dose (TreatmentNaïve)||Duration of effect (in hours)||Notes|
|Immediate-release||10-30 mg every 3-4 hours as needed||3-6|
|Controlled-released (MS Contin, Oramorph SR)||15 mg two times a day||8-12|
|Sustained-release (Kadian)||30 mg one to two times a day||12-24|
|Extended-release (Avinza)||30 mg once a day||24|
|Immediate-release||2-4 mg every 3-4 hours as needed||3-6|
|Extended-release (Exalgo)||8 mg every 24 hours||24|
|Immediate-release||5-15 mg every 4-6 hours||3-6||Often combined with acetaminophen or aspirin|
|Controlled-release (OxyContin)||10 mg two times per day||8-12|
|Extended-release (with acetaminophen) (Xartemis XR)||15 mg oxycodone with 650 mg acetaminophen every 12 hours||8-12|
|Immediate-release||5-10 mg every 6 hours||4-8||Combined with acetaminophen or ibuprofen|
|Extended-release (Zohydro ER)||10 mg every 12 hours||12|
|Fentanylpatch||25 mcg per hour changed every 72 hours||48-72 (12 hours after removal)||Not for opioidnaïvepatients, or acute pain; onset 12-24 hours.|
|Immediate-release (Opana)||5-20 mg every 4-6 hours||4-6|
|Extended-release (OpanaER)||5 mg tow times a day||12|
|Methadone||2.5 mg every 8-12 hours||First dose 4-8 hours, up to 48 hours with repeated doses||High risk for overdose partly due to the long half-life; prescribed only by a trained prescriber|
|Immediate-release (Nucynta)||50-100 mg every 6 hours||3-6|
|Extended-release (Nucynta ER)||50 mg every 12 hours||unsure|
|Immediate-release (tramadol) ||50-100mg every 4-6 hours||4-6||Max dose 400 mg/day|
|Extended-release (UltramER, ConZip)||100mg one a day||Unsure||Max dose 300 mg/day|
Oxymorphone, a schedule II medication, can be given intravenously, subcutaneously, intramuscularly or orally. For acute pain, the immediate-release tablet (Opana) is used at 5-20 mg every 4-6 hours as needed for opioid naïve patients. For those with chronic severe pain, the extended release tablet is used (Opana® ER) and is started at 5 mg every 12 hours and may be titrated up at 5-10 mg increments every 12 hours every three to seven days.
Opioid Dosing in Pediatrics
Many narcotics are available in liquid form for pediatric use. Acetaminophen with hydrocodone is available as an elixir. Acetaminophen with oxycodone and oxycodone alone are also available in liquid form. The dose is based on the oxycodone and is dosed at 0.05 to 0.15 mg/kg/dose every 4-6 hours to a maximum of 5 mg per dose. Morphine is available as an immediate release formulation and is dosed at 0.2 to 0.5 mg/kg every 4-6 hours to a maximum of 30 mg per dose. Hydromorphone is dosed at 0.05 mg/kg