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10 Articles in Volume 6, Issue #3
A Muscular Approach to Headache
Adjuvant Analgesia for Management of Chronic Pain
Breakthrough Pain In Non-Cancer Patients
Case Presentation of Munchausen Syndrome
Electroanalgesic Medical Device
On Knowing
Opioid Malabsorption: Can You Stomach This?
Sedation Safety and Comfort
The American Board of Independent Medical Examiners (ABIME)
The Role of MMPI-2 in Assessment of Chronic Pain

Adjuvant Analgesia for Management of Chronic Pain

An updated review of traditional adjuvant analgesics, psychotropic agents in pain management, other newer medications on the market, and non-pharmacological adjuvant modalities for pain.

 To date, clinical pain practice relies on opioids as the primary analgesics for the management of moderate to severe pain. Adjuvant analgesics use has become increasingly important especially in the management of mild to moderatepain. Adjuvants act on either the excitatory (e.g., substance P, and glutamate), inhibitory neurotransmitters (e.g., GABA), or on neurotransmitters that modulate pain experience (e.g., serotonin, norepinephrine).

Traditional Adjuvant Analgesics

Traditional adjuvant analgesics such as the NSAIDs, acetaminophen, and muscle relaxants will be briefly described first before discussing the newer adjuvants.

  • NSAIDs and Acetaminophen. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. It is important to note that Acetaminophen is not an anti-inflammatory medication. Along with mild narcotics, NSAIDs remain the mainstay of treating mild pain. They are usually well tolerated and are often used to address inflammatory processes, such as muscle aches, strains, or sprains. NSAIDs, as a class, have analgesic, antipyretic, and anti-inflammatory effects although not all of them are FDA-approved for analgesia use. They have the advantage of a very low short-term side-effect profile that does not impact the patient’s lifestyle. They are called non-steroidal because no steroid agent is present in them. Aspirin, for decades now, remains the prototypical agent. Other examples include ibuprofen (Advil, Motrin), naproxen (Naprosyn), and indomethacin (Indocin). NSAIDs can be used synergistically with opioids and for pain not responsive to opioids alone–especially in patients with bone pain and incidental pain. Unlike opioids, NSAIDs do not cause ileus or sedation. Acetaminophen is recommended by the American Geriatrics Society (AGS) as the drug of choice for mild to moderate musculoskeletal pain. It has an excellent safety profile at therapeutic doses that can be up to 4000 mg/day. Toradol (Ketorolac) is an injectable NSAID that is a potent analgesic (30 mg is roughly equivalent to 7-10 mg of morphine) but has the potential for gastric irritation and possible bleeding.1
  • COX-2 Inhibitors.Celecoxib (Celebrex) and rofecoxib (Vioxx) mainly inhibit the enzyme cyclo-oxygenase-2 (COX-2) and thereby result in anti-inflammatory effects with no, or much less, gastric and renal side effects. They reportedly have fewer drug interactions and have no effect on platelet aggregation or bleeding time commonly found with traditional NSAIDs. COX-2 inhibitors are not free of side effects and package inserts should be read thoroughly before prescribing these drugs. Both rofecoxib and valdecoxib (Bextra) have been taken off the market because of concerns of potential side effects. Meloxicam (Mobic) is not a typical COX-2 inhibitor although some have called for re-classifying it as such.
  • Muscle Relaxants. Skeletal muscle relaxants are used to ‘relax muscles,’ relieve stiffness, and decrease pain and discomfort caused by strains, sprains, or other injury to muscles or joints. However, they do not take the place of rest, exercise, physical therapy, or other modalities. Commonly used drugs in this class include: baclofen (Lioresal), carisoprodol (Soma), cyclobenzaprine (Flexeril), diazepam (Valium), methocarbamol (Robaxin), orphenadine (Norflex), metaxalone (Skelaxin), and tizanidine (Zanaflex). They all act on the central nervous system (CNS) to produce their depressant effect. It is important to note that, since muscle relaxants act centrally, they indiscriminately relax all muscles and leave the injured area exposed to reinjury if used for long term. It is strongly recommended they be used for a short-term basis only. Note that sudden cessation of the use of baclofen has been associated with withdrawal symptoms and signs.

Tizanidine (Zanaflex) is a centrally acting agent and also is an alpha2-adrenergic agonistic that may contribute some analgesic properties. It is used for acute low back pain, acute musculoskeletal neck pain, and chronic tension headache. This agent has a reversible liver toxicity and should be used with caution. Cari-sporodol (Soma) is a popular muscle relaxant with an active byproduct metabolite, meprobamate—a barbiturate—that is potentially addictive. The use of alprazolam (Xanax) as a muscle relaxant is not clinically warranted.

Psychotropic Medications

Psychotropic drugs have increasingly been used in the management of chronic pain. The value of psychotropic medications lie in their capacity to modulate pain experience and to treat symptoms which trigger, exacerbate, or compound the effects of pain—notably depression, anxiety, sleep disturbance, anger, and other states of neural excitation. Classes of psychotropic medications commonly used in pain management include: antidepressants (ADs) and anti-epileptic drugs (AEDs). Other psychotropic drugs that are used clinically include anti-anxiety agents, stimulants, and major tranquilizers.

  • Antidepressants (ADs). Current research suggests that several antidepressant effects on pain are mediated by the blockade of norepinephrine and serotonin reuptake thereby resulting in increased levels of these neurotransmitters and enhancing the activation of the descending inhibitory neurons.2 Serotonin, acetylcholine, and histamine have been identified as pain mediators.3 In addition to activating primary afferent nerve pathways via 5-HT3 receptors, serotonin produces mechanical hyper-algesia by acting at a different receptor in the periphery—most likely the 5-HT1a receptor subtype.4 Beta-adrenoceptors have been demonstrated to mediate the analgesic effects of desipramine and nortriptyline.5 ADs have been successfully used to treat chronic headaches (migraine, cluster, and tension), peripheral neuropathies, facial neuralgias (herpes zoster etc.), and neuropathic lower back pain.6 Excellent reviews of the use of ADs in pain management are available.2,7 Tricyclic anti-depressants (TCAs) are the most tested including amitriptyline, desipramine, imipramine, and nortriptyline. Among 48 adequately-controlled trials on TCAs, 46 resulted in a statistically significant benefit in pain relief when compared to placebo.8 Although ami-triptyline or other TCAs with similar pharmacological profile are most widely used, randomized controlled trials have not demonstrated consistent differences between these agents.9 They have been most effective in relieving neuropathic pain and headache syndromes, with analgesic activity independent of effects on mood.5 Randomized controlled trials and meta-analysis have concluded that TCAs are the only agents proven to benefit Post–herpetic Neuralgia.10 A recent double-blinded controlled trial of nortriptyline for chronic low back pain patients without depression resulted in significant reduction in pain intensity.11 Unlike opioids and NSAIDS, therapeutic benefit of TCAs and other ADs may often require several weeks to take effect. Over 60% patients reported improvement in the third week of treatment with serum level in the lower end of the therapeutic range for depression (100-250 mg of mean daily dosing).12 Desipramine and nortriptyline have fewer anti-cholinergic and cardiac side effects leading to better compliance as compared to clomipramine, amitriptyline and doxepin.13

    Selective Serotonin-Reuptake Inhibitors (SSRI) have been studied for a variety of pain conditions but the results are equivocal to date.14,15 Clinical trials do not support the use of SSRIs as first line adjuvant analgesics in pain management and should generally be considered only when other reasons preclude the use of TCAs.16 Other classes of ADs show good potential for pain management even though they have been less studied. Norepinephrine and dopamine reuptake inhibitors such as bupropion can produce anti-thermal nociception.17 Buspirone has been found effective as prophylaxis for chronic tension-type headaches.18 Monoamine oxidase inhibitors have been found to decrease frequency and intensity of migraine.19 Venlafaxine, a serotonin, and norepinephrine reuptake inhibitor, having fewer side effects, actually reverses hyperalgesia and even prevents its development.20 Nefazodone has both analgesic and opioid potentiation effects.21 In general, TCAs are used as first line medications among the ADs. Venlafaxine, nefazodone, mirtazapine and SSRIs may be used as second line agents when tricyclics are not a good option due to excessive anti-cholinergic or other side effects or contraindications (cardiac issues, advanced age, risk of falls). Other intended treatment effects could determine choice of AD. The clinician should not strictly rely on the authors’ recommendations but instead should use his/her judgment in picking the right agent for patients; individualizing management is key.

  • Anti-epileptic drugs (AEDs). Like ADs, AEDs have a role in pain management but, due to safety and side effects, their use has been limited to situations where it is most indicated, namely, in the management of neuropathic pain. The newer agents are much safer and, with few exceptions, preclude the necessity of monitoring blood levels. AEDs act by blocking sodium channels in order to provide pain relief.22 AEDs can also be used as mood stabilizers which, in turn, may have beneficial effects on pain management. Mood stabilization is accomplished via anti-kindling effects, enhancement of GABAergic transmission, diminished excitatory amino acids, and inhibition of voltage-sensitive Na+ channels.23

    Carbamazepine (Tegretol), is the most widely studied AED and demonstrates effective treatment of neuropathic pain.24 AEDs have many other pharmacological actions that may produce analgesia thus making them potential treatments for a variety of chronic pain conditions. Unfortunately, use of carbamazepine is limited by intolerable side effects such as sedation, ataxia, aplastic anemia, agranulocytosis, leukopenia, nausea, and vomiting. Neurotoxicity can lead to acute overdose, stupor, coma, seizures, respiratory depression, vertigo, and blurred vision.25 Drug interactions of carbamazepine with other drugs are also common. For instance, propoxyphene will decrease carbamazepine metabolism while phenytoin (Dilantin) and TCAs will increase it. Similarly, phenytoin has multiple side effects with a profile worse than carbamazepine and should only be used as a second choice.

    Valproate is used prophylactically for chronic migraine but is ineffective for acute migraine.26 Although generally well tolerated, valproate requires regular monitoring due to potential hepatoxicity and bone marrow suppression.27

    Gabapentin (Neurontin) has been reported in open trials to reduce the pain of neuropathic states such as diabetic neuropathy, multiple sclerosis, migraine, post-herpetic neuralgia, and sympathetically-mediated pain.28 It may also be useful for phantom limb pain. Gabapentin has a wide therapeutic window and comparable efficacy with other AEDs and can be prescribed without the need for blood monitoring. Sedation can be reduced by starting therapy at 100 mg tid and titrating 100mg up to 3,600 mg/d. Studies have shown that gabapentin can reverse cold and tactile allodynia as well as heat hyperalgesia.29 In contrast to gabapentin, lamotrigine (Lamictal) reversed cold but not tactile allodynia.30 Other newer AEDs, including zonisamide (Zonagran); felbamate (Felbatol); topiramate (Topomax); levitiracetam (Keppra); tiagabine (Gabatril); and oxcarbazepine (Triliptol), may have a role in difficult to treat pain cases. The newer AEDs have not been as well tested for humans and most of the efficacy data has been based on animal studies. Until there is more human data, it is best to avoid agents like felbamate that have the risk of aplastic anemia and liver dysfunction. A better side effect profile agent in this class is oxcarbazepine, which is a keto-analog of carbamazepine, allows twice daily dosing, has no autoinduction, and is better tolerated than carbamazepine. Topiramate (Topomax) works via sodium channel blockade, GABA potentiation, and glutamate antagonism and has the added potential benefit of weight reduction.31 Tiagabine (Gabatril) blocks GABA reuptake but there is currently little data on its utility with chronic pain. A multi-center trial is currently ongoing.32

  • Pregabalin. This recently launched medication binds, with high affinity, to the alpha2-delta site in central nervous system tissues. In vitro, Pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of the calcium channel function. It has been FDA-approved for use in the treatment of diabetic peripheral neuropathic pain and post-herpetic neuralgia, but many clinicians have already started using it for other forms of neuropathic pain, and even as a mood-stabilizing agent. It is also indicated for use in adults with partial onset seizures.33

  • Anti-anxiety medications. Despite the paucity of efficacy data, benzodiazepines (BZs) have been widely prescribed for pain management–primarily for anxiety reduction and sleep improvement in patients with chronic pain.34 BZs bind to the “benzo”-GABA-chloride receptor complex, facilitating the action of GABA on CNS excitability.35 BZs possess anxiolytic as well as antispasmodic, sedative/hypnotic, and anticonvulsant effects. Valium and other BZs have been used as muscle relaxants. All BZs are equally effective for reducing anxiety. The selection is determined by the desire for short, intermediate, or long acting effects. Clonazepam has been used to treat neuropathic pain and myoclonus, and the episodic lancinating variety of phantom limb pain.36 BZs have also been used to detoxify patients from sedative/hypnotic medications. An extensive review of BZs indicated that they were found to be effective in only a small number of chronic pain conditions such as trigeminal neuralgia, tension headaches, and temporomandibular disorders.37 Whereas the benefits of BZs are difficult to document, the negative effects have been well researched. They extend beyond the usual concerns of abuse, dependence, withdrawal, and secondary effects on mood. The elderly are particularly sensitive to the adverse effects of sedation and cognitive compromise.38 BZs have also been associated with exacerbation of pain and interference with opioid analgesia.39 Alprazolam (Xanax) is a very fast acting BZ with short half-life that poses high potential for abuse and withdrawal. It should be avoided except when a temporary fast-acting anxiolytic effect is desired.

    Anti-anxiety agents that are not BZs are also available and should be considered. These include buspirone (Buspar), hydroxyzine (Atarax), diphenylhydramine (Benedryl) and beta-blockers such as propanalol (Inderal) and atenolol (Tenormin). These medications can produce anxiolytic effects without the cognitive, sedating, and addiction potential of BZ’s.

  • Amphetamine. Amphetamine has been used to enhance morphine analgesia, and to decrease morphine-related side effects such as nausea, sedation, constipation, and loss of alertness. As a class, amphetamine is not widely used due to the risk of increased tolerance and dependence in chronic use, and the potential for withdrawal. Amphetamines can increase blood pressure and exacerbate an underlying coronary artery disease.

  • Hypnotics/Sedatives. A common problem associated with chronic pain is the inability to have a restful sleep. The resulting decreased capacity for the body to recuperate and to rejuvenate inevitably adds to the suffering of patients with chronic pain. Sleep management is, therefore, an essential part of pain management. Most commonly prescribed hypnotics include the benzodiazepines, chloral hydrate, zopiclone, and zolpidem. Hypnotics suppress the reticular formation of the midbrain resulting in sedation, sleep, or anesthesia. BZs bind to the BZ-GABA-chloride receptor complex in the brain while zolpidem binds selectively to GABA A1 receptors. There are multiple categories and etiology for sleep disorders. Use of hypnotics is not recommended for treating sleep irregularities for more than one or two weeks. Adverse side effects may include daytime sedation, anterograde amnesia, rebound insomnia and, for high dosage, impaired respiration, and blood pressure. Discontinuation may produce withdrawal, rebound, and relapse. Drug interaction profiles should be considered when prescribing hypnotics. Sleep problems, which persist after the pain is treated, should be referred to a mental health clinician and/ or sleep laboratory. Provigil (Modafinil), a novel wake-promoting agent, has recently been added to the list of adjuvants for treating sleep-wake problem. Modafinil has been shown to subjectively and objectively improve wakefulness, vigilance, mood, and cognitive performance.40

“The value of psychotropic medications lie in their capacity to modulate pain experience and to treat symptoms which trigger, exacerbate, or compound the effects of pain–notably depression, anxiety, sleep disturbance, anger, and other states of neural excitation.”

Other Adjuvant Analgesics

  • Antiarrhythmics. Current research supports the use of mexiletine as an effective treatment for neuropathic pain.41,42 In one double-blind crossover study, mexiletine not only decreased pain but also the accompanying parasthesias and dysesthesias.43 Another study found mexiletine decreased pain and sleep disturbances associated with painful diabetic neuropathy.44 This agent is not free of side effects and should be used carefully.
  • Calcium channel blockers. Verapamil is a calcium channel blocker commonly used to treat chronic pain and has been successfully used to treat migraine and cluster headaches.45 It is unclear whether the mechanism of action is primarily related to cerebral artery vasodilatation or interaction with serotonergic systems.
  • Ketamine. Ketamine is an ideal anesthetic agent that works on the NMDA receptors. It can be used to treat cancer and non-cancer pain and may be indicated for long term palliative care situations as well. A starting dose of 150 mg/day for subcutaneous infusion or 1 mg every 12 hours intrathecally has been suggested.46 More clinical trials are needed to justify more routine use in the management of chronic pain. The topical form of this medication is clinically used. In the authors’ experience, Ketamine can be used in highly opioid-dependent patients undergoing major surgeries.
  • Lidocaine. Systemic administration of lidocaine can produce sodium channel blocking activity leading to analgesia. Pain with a more central mechanism, such as neuropathic pain and phantom pain, seems to respond better. Low rate infusions have been used as a third or fourth line of treatment especially in opioid–tolerant patients. Incremental rate infusions over 20 to 30 minutes can be used as a therapeutic test before starting mexiletine in patients where anti-epileptic drugs have not been effective.47 Cardiac monitoring is mandatory when using this medication. The idocaine (Lidoderm) 5% patch is a transdermal method of delivery for this local anesthetic. Each adhesive patch contains lidocaine 700 mg (50 mg per gram adhesive) in an aqueous base. It also contains methyparaben and propylparaben as preservatives. The patch is applied once for up to 12 hours in a 24 hours period.
  • Capsaicin. Capsaicin can be used as a topical ointment against neuropathic pain. It acts by inhibiting substance P formation at the skin. It is effective in only 50% to 60% of patients.48 This agent can take up to a week to start working and the patient should be advised of this lag time.
  • Tramadol. Tramadol is a synthetic analog of codeine. It binds weakly to mu-opioid receptors and inhibits serotonin and norepinephrine reuptake. It has been used to treat restless leg syndrome. It has less abuse and addiction potential than other opioids but seizures have been reported with its use.
  • Botulinum toxin. This drug blocks pre-synaptic release of acetylcholine. The neurotoxin type A is used clinically while the type B is still in development. Therapeutic effects last 3-4 months and are achieved through the sprouting of new nerve terminals.
  • Miscellaneous Drugs. Certain radiopharmaceuticals (Strontium 89, Sumarium) have been used, with success, in advanced and palliative cancer pain patients. Recent studies have also concluded that Pamidronate (Aredia) or other bisphosphonates should be used routinely for metastatic bone disease, especially in breast cancer.
“To the extent that emotional states can affect pain experience, interventions aimed at altering such states—or aimed at teaching patients to alter such states—can have analgesic effects.”

Non-pharmacological Adjuvant Analgesics

To the extent that emotional states can affect pain experience, interventions aimed at altering such states—or aimed at teaching patients to alter such states—can have analgesic effects. Psychological therapies such as cognitive behavioral therapy, stress, anxiety, and anger management would fall under this rubric. It is not the purpose of this paper to cover these therapies which have been well discussed elsewhere.49 Similarly, nerve blocks used by anesthesiologist and modalities used in physical medicine and rehabilitation are discussed in their respective texts. Selected modalities are described in this paper because of their popularity and to enhance and update the reader’s knowledge of these modalities.

  • Electrical Stimulation. Spinal Cord Stimulation. Electrical stimulation of the spinal cord and peripheral nerves and receptors is a direct outgrowth of the gate control theory. Long-term electrical stimulation of the spinal cord produces substantial analgesia below the stimulated spinal cord segments in some patients with chronic pain. It is postulated that analgesia results from both stimulation of large ascending tracts and blockade of spinothalamic pathways.50 This procedure has good short-term efficacy but long-term efficacy has yet to be demonstrated. Its high cost would likely limit its use as other less intrusive and less costly alternative management tools become available.

    Transcutaneous electrical nerve stimulation (TENS). TENS has been widely used in the management of chronic pain and is well accepted by patients and physicians. While spinal cord stimulation is an invasive and costly procedure, TENS is less intrusive and involves only surface stimulation. Typically, electrodes are placed on the site of the most severe pain and moved around as needed to optimize pain relief. The use of high frequency TENS was originally based on the gate control theory, which suggested that counter-stimulation of the nervous system would modify pain perception. Later studies suggested that with low frequency, high amplitude (“acupuncture-like”) stimulation, TENS could also raise endorphin levels in the spinal fluid.51 Despite its wide use, there is meager evidence from controlled clinical trials of the efficacy for treating chronic pain. A controlled trial at the Seattle Veterans Affairs Medical Center concluded that, for patients with low back pain, TENS is no more efficacious than placebo, and does not add any benefit to exercise alone.52

    Cranial Electrical Stimulation (CES). Another form of electrical stimulation is the use of micro-current therapy, also known as cranial electrical stimulation (CES). This procedure has a solid history of research in its application to sleep by Russian scientists. It is purported to have a different mechanism of action than TENS. Researchers have claimed success in treating diverse disorders, including depression; anxiety, insomnia, and psychosis.53 A recent review concluded that CES is highly effective in the treatment of chronic pain.54 Efficacy for treating pain has been documented for headaches,55 as well as intractable pain conditions not responsive to other treatments.56 It has been used to increase potency of nitrous oxide in dental procedures,57 and to decrease narcotic requirements during neuroleptic analgesia and surgery.58 Although a recent double-blind controlled study, using veterans who suffer from long-term, severe, intractable pain, has failed to support the efficacy of this procedure,59 another double-blind control study of patients with fibromyalgia reported that three weeks of CES treatment resulted in 28% reduction in tender point scores and a 27% reduction in self reported pain scores. The researchers concluded that it is as effective as drug therapies.60 Thus, CES appears promising as a non-pharmacological treatment for chronic pain in clinical practice.

  • Biofeedback. Biofeedback is a procedure that has been widely used in the management and rehabilitation of patients with chronic pain. It is the treatment of choice for Raynaud disease. In myofascial pain syndromes, surface EMG offers an objective way of documenting the presence of trigger points, and of re-regulating the dys-regulated muscle. It has been widely used to treat tension and migraine headaches. EMG electrodes are placed on the involved muscle and the patient is taught to reduce muscle contractions thru a feedback procedure. Biofeedback for migraines involves learning to control blood flow in the hands or the temple area as a way of impacting pain. Numerous studies have documented improvement rates of 45-55 percent for migraines and 46-57 percent for tension-type headaches.61 It has been used in other pain related disorders where there is a muscle component (e.g., TMJ, back pain), a vascular component (e.g., diabetic neuropathy), anxiety, and stress component (many pain conditions fall in this category).

  • EEG Biofeedback. EEG biofeedback is a new addition and, therefore, much fewer research studies have been done on its application and efficacy in pain management. Case reports have accrued on its effectiveness for fibromyalgia62 and phantom limb pain.63 A combination EMG-EEG biofeedback protocol has resulted in significant improvements in self reported pain and associated physical and psychological symptoms among fibromyalgia patients. One EEG biofeedback protocol—the alpha-theta protocol—trains patients to go into a deep meditative-hypnotic state. It is well known that a deep hypnotic or meditative state can significantly alter pain experience. To the extent that EEG reflects the experience of pain in the brain, this modality has potential application. The applicability of biofeedback also extends beyond the specific focus on pain reduction. Many chronic pain patients are depressed, angry, anxious, and exhibit other psychiatric symptoms that, in turn, may exacerbate pain. Biofeedback can train patients to reduce bracing of posture and improve self-regulation of body physiology that impacts pain. The drawback is that biofeedback often requires multiple sessions and trained personnel to administer.

  • Hypnosis. Hypnotic analgesia has been widely studied.64 Although the specific mechanism of action is still being debated, increased susceptibility to hypnotic suggestion in a hypnotic state has been repeatedly observed and accepted as a legitimate phenomena. Hypnotic analgesia is complex and research to date indicates that there are probably multiple factors and mechanisms involved, including selective reduction of pain-related affect, reductions in sensory pain, and inhibition of pain signal at the spinal level of processing. It is beyond the scope of this paper to discuss hypnotic analgesia in detail. The reader is referred to an excellent text entitled “Hypnosis and suggestion in the treatment of pain” by Joseph Barber.64

  • Relaxation therapy.Relaxation therapy is a systematic approach to teaching patients to gain awareness of their physiological responses and achieve both a cognitive and a physiological sense of tranquility without the use of machinery employed in biofeedback. The most commonly used include progressive muscle relaxation, meditation, autogenic training, and guided imagery. Relaxation therapy has been most widely tested with chronic tension headaches, chronic vascular headache, and low back pain. Unlike biofeedback and hypnosis that require specialized training, relaxation therapy can be easily learned and taught to patients. For more information, the reader is referred to Blanchard’s section of the text “Psychological Approaches to Pain Management.”65

Last updated on: January 6, 2012
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