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Nee.broadcastmed.netJerome Schofferman, MD
Spine Care Medical Group
Long-term Opioid Therapy vs
Carol Hartigan, MD
New England Baptist Hospital,Harvard Medical School Therapy for Refractory Chronic
Low Back Pain
SpineLine Section Editor:
Robert J. Gatchel, PhD, ABPP
University of Texas at Arlington
A 50-year-old Caucasian man presents with severe nonradiating low back pain, which he has had for five years. He began noticing pain after a long airplane ride, with no other precipitating injury or event. He denies any weakness or numbness in his lower extremities, or any bowel or bladder symptoms. His physical examination demonstrates muscle hypertonus and tenderness diffusely over the lower lumbar spine and para- lumbar areas. Lumbar flexion is painful and limited to 60° with extension less painful but also limited to 5°. Straight leg raising produces low back pain bilaterally and is limited to 60° on each side. Neurological examination of the lower extremities reveals 1+ reflexes bilaterally and symmetrically, with normal sensory and motor examinations, although pain limits manual muscle testing.
He states that the pain is getting worse and reaching the point that he is seriously WHERE DO YOU STAND?
considering taking early retirement from his position as a CEO for a major oil company. In each issue of SpineLine, this He was an athlete in his younger days and up until one year ago, still played tennis column presents responses to a and golf, but he cannot participate now secondary to pain. "If I have to live like this controversial case from two or for the rest of my life, I'd rather not," he tells you.
more spine care physicians. Let He has had a detailed structural evaluation. Lumbar magnetic resonance imag- us know where you stand by ing (MRI) demonstrates moderate to severe spondylosis at L3-4, L4-5 and L5-S1. taking the survey at the end of Three level lumbar facet injections and a series of two lumbar epidurals did not this article. Respond on www.
significantly relieve his pain, although he states that the first lumbar epidural steroid spine.org or fax your response injection brought his pain down slightly for one day after the procedure. Lumbar to (708) 588-1080. We'll report discography/CT showed posterior epidural flow at L3-4 and L5-S1, with concor- the results in the next issue. (See dant pain at L4-5 and L5-S1. He has had 12 months of chiropractic care, now gets results from last issue's question weekly massages and works out with a trainer three times a week. Prior to using at the end of this case.) the trainer, he was in a supervised physical therapy program for three months. At this point, he is seriously considering curtailing the physical training because of SEND US YOUR IDEAS
the gradual worsening of his pain. He was initially prescribed nonsteroidal anti- If you have a controversial topic inflammatory medications and Skelaxin,™ which helped for a few years. He then was or case you'd like to see tried on tramadol, which helped "take the edge off" initially but is now less effective. discussed in this column, please Within the past year, a series of three fluoroscopically guided epidural steroid injections provided several weeks of partial relief and bilateral, three-level zygapophysial medial branch blocks were nondiagnostic. Up until now, he has avoided trying stronger opioid attn: Pamela Towne medication (although it has been discussed with him) because he "doesn't want to get Fax: (708) 588-1080 hooked," but he is now changing his mind. Is it in this gentleman's best interest to be E-mail: email@example.com treated with long-term opioid therapy? November/December 2006 Jerome Schofferman, MD, Responds
use of a psychoactive substance, characterized by an abstinence This patient presents an all too common problem. A middle- syndrome when the substance is abruptly stopped or the dose aged man has deteriorating function caused by increasing is abruptly and significantly reduced. Dependence is usual in chronic low back pain (CLBP). He has three abnormal motion patients treated with opioids, but it is rarely a clinical problem. segments. He has failed to respond to moderately aggressive There may be a fear of disciplinary action. Many medical boards, care, including low potency opioids. Further injections are medical societies and the DEA have issued position papers that not likely to help, nor is time on his side. His options include it is considered appropriate medical practice to prescribe long- a three-level lumbar fusion, a functional restoration program term opioids for chronic pain,19,20 and physicians who prescribe (FRP) with cognitive-behavioral support or long-term opioid opioids for appropriate clinical indications are acting well within analgesic therapy (LTOAT). The advice we give him must be the scope of good medical practice.
evidence-based, with the best research evidence being most Efficacy of Long-Term Opioid Analgesics
The published evidence available currently is insufficient in Patients with CLBP
to support a three-level fusion for CLBP. Even expert opinion The major concern then should be efficacy. Several Level I and would be conflicting at best. The Level I evidence available II studies show that opioid analgesics are effective for CLBP, at currently is sufficient to support a Grade A recommendation least in the short-term.5-11 There is sufficient consistent evidence for a 70- to 80-hour FRP.1-3 It is not likely that less intense of long-term efficacy (one randomized controlled trial [RCT],6 rehabilitation would help this patient given that he already had one prospective case series18 and one retrospective series17) three months of physical therapy, continues to exercise regularly to make a Grade B recommendation. In addition, there is no and does not appear to have significant fear-avoidance.4 There evidence that suggests loss of efficacy over time unless there is sufficient Level I and II evidence to make a Grade A or B is disease progression.14,17,18 Finally, there are multiple Level recommendation that opioid analgesics are effective and safe for I and II studies that show the efficacy of opioids for chronic CLBP.5-11 Therefore, it is best medical practice, well-supported noncancer pain, and each of these studies contains many pa- by the evidence, to offer this patient a therapeutic trial of opioids tients with CLBP.21-23 A brief review of some of the studies is and, if there is significant improvement, LTOAT.
Any negative bias against LTOAT appears to have been based Hale and associates performed an 18-day multicenter RCT on anecdotes, not evidence. In fact, several recent surveys have in 213 patients with CLBP, and compared oxymorphone-ER, suggested LTOAT may now be the standard of care for well- oxycodone-CR and placebo.5 During the titration phase, about selected patients with refractory moderate to severe CLBP in 15% of opioid-treated patients withdrew because of side effects primary care and some spine specialty practices.12-14 In one uni- and another 4% withdrew because of lack of efficacy. In the versity health system, 38% of patients with CLBP were treated placebo group, 57% withdrew because of lack of efficacy, and with opioids. Of those prescribed opioids, 9% of patients were 1% because of side effects. Both opioids proved better than given more than a three-month supply.12 In a university ortho- placebo and no differences were reported between opioids. pedic spine clinic, opioids were prescribed for 66% of patients, About 35% of both opioid-treated groups described their pain of whom 25% were treated with opioids long-term.14 as absent or mild, compared to only 12% in the placebo group. Sixty-one percent of the opioid groups reported moderate to Controversies in Long-Term Opioid
complete pain relief versus 28% for placebo. Conversely, 45% of the placebo group described their pain as severe versus 14% Concerns about LTOAT have been expressed and analyzed.15 in the opioid groups. Improvements were statistically signifi- Organ toxicity is rarely, if ever, seen. Although side effects are cant in general activity, mood, normal work and enjoyment of common, opioids are far less toxic than NSAIDs and many other life, but not walking ability. No instances of addictive behavior medications.16 Tolerance is not a problem clinically. Opioids were reported. Side effects were common, but only sedation and are effective long-term in patients with cancer unless there is constipation were more frequent in the opioid groups compared disease progression.14,17,18 The evidence supporting long-term to placebo.
use for CLBP is fair, but there is no evidence of loss of efficacy Allan et al6 performed a 13-month unblinded randomized over years unless there is disease progression.14 Any controversy parallel group study to compare titrated doses of transdermal about addiction and dependence may be a result of misunder- fentanyl to sustained release oral morphine in 650 patients with standing. Addiction is a neurobiologic disease characterized by CLBP. Of the 650, 31% – 37% withdrew because of adverse the compulsive use of a psychoactive substance despite biologi- events. The drugs provided similar results. Depending on level cal, psychological or social harm. There is loss of control and of activity, 50% – 65% of patients described themselves as im- craving. The prevalence of addiction in patients treated with opi- proved and 37% – 53% of patients had at least a 50% reduction oids for pain is the same as it is in the general population—about in pain. SF-36 mean quality of life scores showed improvements 10%. Dependence is a physiological state induced by the chronic in physical functioning, role-physical, bodily pain, vitality, so- November/December 2006 cial function and role-emotional. Over the 13-month period of pain, 12 of whom had reported refractory CLBP.22 In 17(35%) the study, opioid doses increased only slightly, usually early in patients pain was reduced from a mean of 7.4 to 2.9 (excellent treatment, attributed to titration to optimal dose rather than responders). In 17 others the pain was reduced from 7.8 to 5.6 (partial responders). In 14 (29%) there was either no meaningful Hale8 performed a 10-day RCT to compare the efficacy and relief or intolerable side effects (non-responders). Patients with safety of titrated doses of either oxycodone-CR or oxycodone- an excellent or partial response were continued on morphine, IR (immediate release) in 47 CLBP patients. Eleven patients but the long-term results have not been published.
(23%) withdrew because of side effects. Equal and significant improvements occurred with both formulations. Pain intensity Summary of Evidence
decreased from moderate to severe at baseline, to slight at the In summary, there is good evidence that opioids can provide end of titration, with both oxycodone formulations. Simpson12 meaningful relief of pain for patients with CLBP in the short- found statistically significant improvement in pain in 50 patients term. About one third of patients get good to excellent pain relief changed to transdermal fentanyl, compared to their prior regi- and another one third fair to moderate improvement. There is mens of pain contingent oral opioids for CLBP. Gammaitoni fair evidence of longer-term effectiveness and no evidence for et al11 prospectively studied 33 patients with refractory CLBP loss of efficacy after 12 to 13 months of treatment. Evidence treated with gradually increasing doses of oxycodone. Pain was for improvement in disability and impairment is fair. Up to one reduced from a mean of 6.4 to 4.4, and worst pain from 7.7 to third of patients cannot tolerate opioids, but there is an even 5.6. Improvements were significant in general activities, mood, higher withdrawal rate because of lack of efficacy for placebo walking tolerance and sleep. Side effects were common, but there patients. Toxicity is nearly absent, but side effects are common. were no serious adverse effects.
The prevalence of mild sedation (usually treated with modafanil), Jamison et al9 performed a small prospective RCT study constipation (readily treated with ordinary laxatives or Mira- comparing naproxen, fixed dose opioid therapy and titrated dose Lax™) and possibly nausea are statistically greater in patients of opioid. The titrated opioid group had better pain control treated with opioids than placebo. The incidence of diversion, and more improvement in mood than the fixed dose group, and addictive behavior or other social problems is very low. both opioid groups reported significant improvements in pain, There is no best opioid. No opioid has been shown to be depression and anxiety compared to the naproxen group. Differ- superior to others in terms of efficacy or side effects. The opi- ences in sleep or activity were not significant among groups. oids that appear most suitable for long-term use are described Schofferman18 reported a prospective case series of 33 pa- in Table 1. There is no way to predict which opioid is best for
tients with refractory CLBP treated with opioids for one year. a particular patient.26 It is not uncommon to have to try several The opioid for long-term treatment was selected by response opioids before finding the most effective one for a particular during the trial phase. Five (15%) patients withdrew because patient. There is no correct dose of opioid and, at least in theory, of side effects. In the remaining 28, there were statistically and no maximum dose as opioids do not have a true ceiling. The dose clinically significant improvements in pain and function at one limit is based on benefits versus side effects, not milligrams. year. The mean Numeric Rating Scale (NRS) levels improved Opioid therapy is not an end unto itself. In addition to opi- from 8.6 to 5.9 and the mean Oswestry Low Back Disability oids, most patients being treated with pharmacological therapy Index (OSI) from 64 to 54. There was a biphasic response. In for chronic pain require other medications. Many patients do 21 patients (responders), there was an improvement of NRS better with the addition of adjunctive analgesics such as the from 8.45 to 4.9. Seven others had no change in NRS. Overall, tricyclic or tetracyclic antidepressants, or anticonvulsants. of the 33 patients who started the study, opioids were beneficial Most need medications to treat the side effects of opioids such in 21 (64%).
as laxatives, anti-emetics or stimulants. All patients need to be Furlan and associates performed a meta-analysis of the ef- encouraged to continue or resume rehabilitation. fectiveness and side effects of opioids for chronic noncancer pain Recommendations for this Patient
that included patients with CLBP.21 Withdrawal rates averaged Based on the evidence, I can make best practice recommenda- 33% in the opioid groups and 38% in the placebo groups. They tions for this patient. I would obtain a psychological evaluation concluded that opioids were more effective than placebo for for three specific reasons. He has said that "he cannot live like pain and functional outcomes in patients with nociceptive pain this." He needs to be evaluated for any suicidal thoughts or (which includes low back pain). With respect to side effects, plans, possibility of depression and for any history of substance only nausea and constipation were clinically and statistically abuse. If there are no psychological contraindications, he should significantly greater in the opioid patients than placebo. be offered a trial of a potent opioid analgesic. However, if anti- The MONTAS (ie, morphine for chronic nontumor as- depressants are recommended, I would consider which to start sociated pain syndromes) study group performed a two-week, first, the opioid or antidepressant, but I would not begin both randomized, prospective, controlled, double blind study of sus- at the same time in order to be able to attribute efficacy or side tained-release morphine in 48 patients with various noncancer effects to each particular drug. November/December 2006 visit periodically to get the family's perspec- Table 1. Opioid Analgesics Most Useful for Chronic Moderate
tive about the response to treatment.
to Severe Pain23-25
Opioid therapy is fully reversible. Sur- Brand Names
gery is not. Therefore, before this patient is offered surgery, he should surely have a • Multiple dose sizes trial of opioid therapy. If the patient does depending on product • Convenient not have an adequate response, and if he is and patient factors • Gold standard given very complete informed consent, then Multiple generics surgery might be an option. Physician exper- tise and patient values are important parts of Generics for most • Five dose sizes evidence-based practice. • Less constipating • Very inexpensive Generic available • Initially more 1. Brox J, Sorensen R, Friis A, et al. Randomized complicated to use clinical trial of lumbar instrumented fusion and • Multiple dose sizes cognitive intervention and exercises in patients Generics for some with chronic low back pain and disc degeneration. • Very expensive 2. Brox J, Reikeras O, Nygaard O, et al. Lumbar • ?Higher abuse instrumented fusion compared with cognitive intervention add exercises in patients with chronic • Only 2 mg dose back pain after previous surgery for disc hernia- Generic available tion. Pain. 2006;122:145-155.
3. Fairbank J, Frost H, Wilson-MacDonald J, et al. • Multiple dose sizes Randomized controlled trial to compare surgical stabilization of the lumbar spine with an intensive rehabilitation program for patients with chronic low back pain. BMJ. 2005;330:1233.
If there is no history of allergy to a specific opioid, the 4. Rainville J, Hartigan C, Martinez E, Limke J, choice, sadly, might be based on his insurance options. Metha- Jouve C, Finno M. Exercise as a treatment for chronic low back pain. Spine J. 2004;4:106-115.
done is the least expensive and a very effective analgesic, but 5. Hale M, Dvergsten C, Gimbel J. Efficacy and safety of oxy- a bit more difficult to use initially. Otherwise, I would start morphone extended release in chronic low back pain: results of with morphine, the gold standard for analgesic treatments. It is a randomized, double-blind, placebo and active-controlled phase most convenient to use the 24-hour morphine. The initial dose III study. J Pain. 2005;6:21-28.
of morphine would be 30 to 60 mg per day. He should also be 6. Allan L, Richarz U, Simpson K, Slappendel R. Transdermal fen- given a prescription for immediate release morphine sulfate (15 tanyl versus sustained release oral morphine in strong-opioid naïve or 30 mg tablets) as rescue doses for breakthrough pain. The patients with chronic low back pain. Spine. 2005;30:2484-2490.
7. Peloso, P, Fortin L, Beaulieu A, et al. Analgesic efficacy and safety dose of extended release morphine would be titrated upward of tramadol/acetaminophen combination Tablets (Ultracet®) in based on pain response, side effects and amount of rescue doses treatment of chronic low back pain: a multicenter, outpatient, needed for breakthrough pain. I would provide a prescription randomized, double blind, placebo controlled trial. J Rheumatol. for a senna-type laxative to be taken prophylactically and an anti-emetic if needed. I would either see him or speak with him 8. Hale ME, Fleisschmann R, Salzman R, et al. Efficacy and safety of on the phone in a week to determine titration of the dose. If controlled-release versus immediate-release oxycodone: random- there was no meaningful response by 120 mg per day, I would ized, double-blind evaluation in patients with chronic back pain. Clin J Pain. 1999;15:179-183. change the opioid and repeat the same cycle. When rotating 9. Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. opioids, I recommend consulting a table of equi-analgesic doses Opioid therapy for chronic noncancer back pain: a randomized for chronic use, begin the new opioid at about 50% of that dose prospective study. Spine. 1998;23:2591-2600. (without the need to taper) because cross tolerance is often 10. Simpson RK, Edmondson EA, Constant CF, Collier C. Trans- incomplete, and increase the dose based on analgesic response dermal fentanyl as treatment for chronic low back pain. J Pain and side effects. Once the best opioid is found, the dose is sta- Symptom Manage. 1997;14:218-224. bilized and any other medications adjusted, the patient should 11. Gammaitoni AR, Gaier BS, Lacouture P, Domingos J, Schlagheck T. Effectiveness and safety of new oxycodone/acetaminophen be seen at least every three months. At each visit, there should formulations with reduced acetaminophen for the treatment of be documentation of analgesic response, functional response, low back pain. Pain Medicine. 2003;4:21-30.
side effects and an inquiry about aberrant behavior. It might 12. Vogt M, Kwoh K, Dope D, et al. Analgesic usage for low back pain: be useful to ask the patient to have his or her spouse attend the impact on health care costs and service use. Spine. 2005;30:1075- November/December 2006 13. Fanciullo G, Ball P, Giralut G, et al. An observational study of the function in the long term, ie, over a period of years rather than prevalence and pattern of opioid use in 25,479 patients with spine weeks or months. and radicular pain. Spine. 2002;27:201-205.
The doses in the case studies discussed above run up to a 14. Mahowald M, Singh J, Majeski P. Opioid use by patients in an or- thopedic spine clinic. Arthritis & Rheumatism. 2005;52:312-321.
maximum analgesic equivalent of approximately 180 mg of 15. Portenoy RK. In Fields HL, Liebeskind JC (eds). Pharmacological morphine per day. The high end dose utilized in these studies approaches to the treatment of chronic pain. IASP Press; Seattle, is roughly equal to 120 milligrams of oxycodone per day, or 24 tablets of 5 mg oxycodone per day.2,3 No studies look at doses 16. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli- equivalent to the higher doses which are currently frequently Goudas M, Chew PW, Lau J, Carr D. Management of opioid side prescribed for "severe" CNMP and CLBP. Anecdotally, it is effects in cancer-related and chronic noncancer pain: a systematic not unusual for my colleagues and me to evaluate individuals review. J Pain. 2003;4:231-256.
17. Collin E, Poulain P, Gauvain-Piquard A, Petit G, Pichard-Leandri who have been receiving a base dose of 80 mg of oxycodone E. Is disease progression the major factor in morphine "tolerance" HCl every eight hours, which is roughly equal to 48 tablets of in cancer pain treatment? Pain. 1993;55:319-326.
5 mg oxycodone per day. These extremely high "base" doses 18. Schofferman J. Long-term opioid analgesic therapy for severe of opioids are usually associated with the addition of prescrip- refractory lumbar spine pain. Clin J Pain. 1999;15:136-140.
tions for short-acting opioids for "breakthrough" pain, leading 19. Medical Board of California. Guidelines for prescribing controlled to total daily doses that are roughly equivalent to three times substances for pain (revised). Action Report: Medical Board of the high end dose utilized in the short term studies. Often California. 2003;87:1-4. 20. Haddox J, Jordanson D, Angarola R, et al. The use of opioids these medications are administered to young individuals with for the treatment of chronic pain: a consensus statement from minimal to moderate magnetic resonance imaging variations the American Academy of Pain Medicine and the American Pain from "normal." Society. Glenview IL. 1997.
Frequently, prescriptions for numerous other "adjunctive" 21. Furlan A, Sandoval J, Mailis-Gagnon A, Tunks E. Opioids for medications are included. Among these are the "membrane sta- chronic noncancer pain: a meta-analysis of effectiveness and side bilizers," including extremely high dose gabapentin, topiramate effects. CMAJ. 2006;174:1589-1594. and pregabalin (LyricaTM), which are used "off-label" for CLBP 22. Maier C, Hildebrandt J, Klinger R, Henrich-Eberl C, Lindena G. Morphine responsiveness, efficacy and tolerability in patients and which are not well studied or FDA-approved for this use. with chronic non-tumor associated pain—results of a double-blind Other adjunctive medications prescribed for CNMP and CLBP placebo-controlled trial. Pain. 2002;97:223-233.
include benzodiazepines, tricyclic anti-depressants and selective 23. Markenson J, Croft J, Zhang P, Richards P. Treatment of persistent serotonin reuptake inhibitors. Often included in the "cocktail" pain associated with osteoarthritis with controlled-release oxyco- are the so-called "muscle relaxants," such as cyclobenzaprine done tablets in a randomized controlled clinical trial. Clin J Pain. and carisoprodol, even though these medications have never been shown to affect or relax muscle and are actually central 24. Marcus D, Glick R. Sustained-release oxycodone dosing survey of chronic pain patients. Clin J Pain. 2004;30:363-366. nervous system sedatives. On occasion, we see the addition of 25. Acherman S, Mordin M, Reblando J, et al. Patient-reported uti- dronabinol (tetrahydrocannabinol, [THC]) for CLBP.
lization patterns of fentanyl transdermal system and oxycodone Many individuals receiving such high dose polypharmaceuti- hydrochloride controlled-release among patients with chronic cal treatment continue to report high levels of pain and extremely nonmalignant pain. J Manag Care Pharm. 2003;9:223-231. low levels of function. Often, they are well under 50 years old. 26. Galer BS, Coyle N, Pasternak G, Portenoy R. Individual vari- One recent study of 196 patients receiving narcotics for CNMP ability in the response to different opioids: report of five cases. for one year found that nearly one third of participants misused the prescribed opioids.4 Misuse occurred through either testing negative for the base prescription medication, testing positive for other prescribed narcotics or for recreational drugs at ran- Carol Hartigan, MD, Responds
dom drug screens (usually cocaine or amphetamines), obtaining It is inadvisable and potentially harmful to offer this 50-year-old prescriptions from multiple providers, forging prescriptions or CEO opioid treatment at this time. The use of opioids in chronic diversion. The risk for drug abuse and addictive behavior in nonmalignant pain syndromes (CNMP), including chronic low the chronic pain population is high. One study of 200 patients back pain (CLBP), remains controversial. Few studies examine with CLBP documented that 36% admitted to a history of drug the use of narcotics for CNMP and CLBP. These studies are abuse which predated the CLBP in 94% of the cases.5 The num- primarily uncontrolled studies which evaluate modest doses of ber of individuals in the US admitting to abuse of prescription narcotics used over a period of weeks or months. For the most drugs increased by 140% between 1992 and 2003.6 The number part, the results demonstrate varying degrees of reduced pain in of prescriptions written for controlled substances in the USA the short run, with mixed results related to function.1 Currently, increased by 154% during the same period.6 The controlled there are no randomized controlled clinical trials demonstrat- prescription drugs most likely to be abused include the opioids, ing that opioid treatment for CLBP reduces pain or increases especially OxycontinTM and VicodinTM. November/December 2006 The long-term physiologic effects of opioids are not well other similar protocols. Treatment goals should be established. studied. Documented side effects include somnolence, depres- A written "opioid agreement" should be obtained and reviewed sion and constipation.1 Individuals using opioids demonstrate periodically. Pain and function should be measured and moni- decreased tolerance for pain, or hyperalgesia.7 Opioids are tored. The therapy should start at low dose and be monitored known to alter the development and function of immune cells, with small increases to a maximum level that is equivalent to and affect the function of both the hypothalamic-pituitary- the moderate doses evaluated in the short-term uncontrolled adrenal axis and the hypothalamic-pituitary-gonadal axis. This studies. Functional goals should be set and their achievement results in decline in plasma cortisol, testosterone, luteinizing required for continued treatment. Discontinuation should be hormone, estrogen and progesterone levels and an increase in advised if adverse effects outweigh benefits, or if little change in prolactin levels.1,8 This hormonal disturbance is associated pain or function results. Unproven, "adjunctive" medications with reduced libido, dysmenorrhea and galactorrhea.9 Man- should be avoided. The "opioid agreement" should include agement of these iatrogenic effects often includes the addition acceptance to undergo random, unannounced urine screening of testosterone to address the reduced libido and/or sildenafil for prescribed medication, along with a toxic screen, and both citrate (Viagra™) to address the reported erectile dysfunction. should be periodically performed on every patient regardless No studies are currently available which examine the long-term of social class or occupation. Careful history to rule out risk side effects of these treatments in the clinical setting of CLBP.
for abuse, diversion and secondary gain should be taken. One Because of a perceived lack of other options, health care physician should prescribe the opioid, not a rotating staff.
providers treating (and individuals experiencing) CNMP or CLBP may consider employing opioids after a course of "con- Recommendation for this Patient
ventional" care fails. When used, the early effects of opioids In the case of this 50-year-old CEO with "moderate to severe" include the induction of euphoria and improved mood, along spondylosis, perhaps equivalent to that of a 70-year-old, I do with reduced tension, pain and anxiety. The pharmacologic not, at this time, endorse the initiation of opioid treatment, phenomenon of tolerance and dependence almost always de- other adjunctive medication or surgery. During his five years velops whereby an increased dose is required to produce an of progressively worsening low back pain, he has clearly not equivalent analgesic effect. Increased tolerance and dependence undergone an adequate physical or behavioral rehabilitation resulting from the increased dose may replace pain as the pri- treatment program. In spite of one year of chiropractic treat- mary problem. Later, attempted reduction in narcotic dose can ment, three months of "physical therapy," visits with a personal be associated with withdrawal symptoms which can manifest trainer three times per week, and once a week massage, his trunk as an increase in the "original" pain complaint. A vicious cycle and lower extremity flexibility are 50% below normal values. may occur when increased pain during attempts to wean opioids During examination, he declines to make an effort to partici- results in a perceived need for continued or increased opioid pate in full muscle testing because of his pain or anticipation dose. This may encourage continued use, increased dose and of pain, although no true radicular weakness is present. Given addition of further "adjunctive" medications. Other chosen these objective physical findings, along with his report of dis- strategies may include drug "rotation" and/or drug "holidays"; continuation of tennis and golf, his consideration of "curtailing neither strategy is well studied. the physical training" and retiring early from his administrative Studies demonstrate that opioid use induces abnormal work, I wonder what he is doing with the trainer and what he pain sensitivity in patients.7,10-12 Patients receiving prolonged did with the physical therapist? I wonder what message he has opioid therapy have been shown to have increased expression received about movement and activity from all of his provid- of the endogenous opioid dynorphin which is associated with ers? The implicit and usually explicit message conveyed when enhanced pain sensitivity.13,14 Morphine turns on medullary discography is recommended and performed is that there is "off-cells" which are inhibitory to pain transmission and inhibit nothing else to offer but surgery or opioids. medullary "on-cells" which are facilitators of pain transmis- Unfortunately, it appears that this gentleman's treatment has sion.15,16 When animals receiving morphine are given naloxone, been suboptimal, though quite standard. In spite of his care, he a rebound facilitation of the pain facilitating "on-cells" occurs. has become severely deconditioned. His physicians, chiroprac- It is hypothesized that when CLBP patients are weaned from tor, physical therapist and trainer have essentially advised him narcotics, the "on-cells" are facilitated. Further, studies suggest to "let pain be his guide." His physical therapy sessions likely that exogenous opioids alter endogenous opioid systems and consisted of the various passive modalities; some simple, basic, produce cross tolerance to endogenous opioids.7 unchallenging floor exercises; and maybe some light resistance There may be a very small number of patients with CLBP equipment exercises. His present poor flexibility is evidence for whom long-term moderate dose opioids may be useful. If that any stretching he performed or passively received was not opioids are prescribed for CLBP, this should be done according aggressive and that improved flexibility was not expected or to the consensus protocol suggested by the American Academy required as a result of the stretching. He may have been given of Pain Medicine together with the American Pain Society17 or advice from health care providers to avoid certain activities November/December 2006 including bending normally, performing light impact activities, him in follow-up to review, modify and adapt the program. It using the stair master ("bad for the SI joint"), the elliptical ma- should be made clear to the CEO that the lines of communica- chine and/or golf. Based on the clinical information, it is likely tion are open for as-needed support. that he is avoiding activities of daily living including carrying After several months of working out independently, the groceries and laundry, emptying the dishwasher, performing CEO's response to optimal rehabilitation should be assessed. yard work, home maintenance and kicking a soccer ball, among If he is doing well and feeling satisfied, the need to consider the other things. The physical therapist and trainer probably made question of opioids and surgery is obviated. If his symptoms attempts at more vigorous conditioning that were followed by remain severe, in spite of full participation in maximum reha- reversal of conditioning goals and expectations when the CEO bilitation, then he is likely a good surgical candidate provided reported pain. At that point, resumption of more passive, less that there are no major psychosocial or medicolegal risk factors provocative treatment likely ensued. It is also possible that the for poor outcome. If he has continued severe pain and declines spine physicians and physical therapist did not communicate re- surgery, then he should be advised to remain as active as possible garding activity and exercise clearance, goals and expectations. in spite of the pain. I would not likely endorse initiating long- This man needs to hear that it is "safe" for individuals with term opioids, but that would depend on what I have learned CLBP to exercise and that exercise does not increase the risk about his psychological, social and functional situation during for future back injury in this population.18 It is advisable that treatment. If, after pursuing a final rehabilitation effort, this this 50-year-old man optimize all physical parameters in spite man requested a referral for medication/opioid management, I of his pain. If he were my patient, I would tell him that I am would refer him to a spine specialist at a reputable pain clinic disappointed with his physical and functional situation, but am who utilizes guidelines similar to those recommended by the optimistic that these can definitely improve with intensive, ex- American Academy of Pain Medicine and the American Pain ercise focused rehabilitation.18-20 I would not be able to predict Society discussed above.17 I would educate him about opioid for sure whether his pain will improve, but studies support that treatment prior to referral. it is likely that he will experience significant reduction in his In any case, offering this 50-year-old man opioid treatment pain with this approach.18-20 In the worst case, he will be doing in advance of these above efforts is inadvisable and potentially better, even if he is not feeling better. If a later decision is made harmful.
to pursue surgery, he will be in better physical shape to undergo surgery and will come out of surgery at a better physical starting References
point. But, I would tell him that now is not the time to focus on 1. Ballantyne JC, Mao J. Opioid therapy for chronic pain. NEJM. surgical considerations or medication management. Now is the time to focus on reversing the deconditioning. 2. Gammaitoni AR, Alvarez N, McPherson MC, Gergmer KS. This CEO should undergo six to eight weeks of a team Clinical application of opioid equianalgesic data. Clin J Pain. (physician and physical therapist) supervised intensive, non- 3. Gordon DB, Stevenson KK, Grieffie J, et al. Opioid equianalgesic pain contingent, quota-based, back- (trunk- or core-) focused conversions. J Pall Med. 1999;2:220-219.
and general exercise program, incorporating a strong cognitive 4. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of behavioral component. Psychologic evaluation with a clinician opioid misuse in patients with chronic pain: a prospective cohort who is experienced in spine medicine is advisable. One study study. BMC Health Serv Res. 2006;4(6):46.
found the 59% of CLBP patients met the criteria for at least 5. Polatin P, Kinney RK, Gatchel RJ, et al. Psychiatric illness and one Psychiatric Axis 1 disorder, the most prevalent of which chronic low back pain. Spine. 1993:18:66-71.
was major depression. The majority of those reporting depres- 6. National Center on Addiction and Substance Abuse at Co- lumbia University. Under the Counter: The Diversion and sion had been depressed prior to the onset of back symptoms.5 Abuse of Controlled Prescription Drugs in the US. July 2005. Strategies for managing expected exacerbations of pain using an active approach should be discussed with the CEO during treat- ment. The physical therapist and physician should recommend 7. Compton M. Cold-pressor pain tolerance in opiate and cocaine and encourage gradual resumption of everyday activities.
abusers. J Pain and Symp Manage. 1994;9:462-473.
The therapy program should be followed by two to three 8. Roy S, Loh HH. Effects of opioids on the immune system. Neu- months of a consistent maintenance workout at a health club. rochem Res. 1996;21;1375-1386.
9. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of During formal physical therapy treatment, this former golfer and long term intrathecal administration of opioids. J Clin Endocrinol tennis player should be given the tools to independently perform a simple, accessible and realistic prescribed exercise program at a 10. Brodner RA, Taub A. Chronic pain exacerbated by long-term nar- health club with certainty and confidence. He should not leave cotic use in patients with non-malignant disease: clinical syndrome physical therapy reliant on the physical therapist and without a and treatment. Mt Sinai J Med. 1978;45:233-237.
concrete plan that he has tested at the health club prior to dis- 11. Taylor CB, Zlutnick SI, Corley MJ, Flora J. The effects of detoxi- charge from therapy. The physician and/or therapist should see fication relaxation, and brief supportive therapy on chronic pain. November/December 2006 12. Savage SR. Long-term opioid therapy: assessment of consequences tion in the US is estimated at $11.7 billion. Thus, a great deal and risks. J Pain Symptom Manage. 1996:11:274-286. of clinical research remains to document the best approach for 13. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and opi- the prevention and development of CLBP, and, once it does ate tolerance; a current view of their possible interactions. Pain. develop, to the effective management of it. In agreement with 14. Bian D, Ossipov MH, Ibrahim M, et al. Loss of antiallodynic and Dr. Schofferman, of the published studies during the last decade antinociceptive spinal/supraspinal morphine synergy in nerve-in- evaluating the efficacy of immediate and extended-release opioid jured rats: restoration by MK-801 or dynorphine antiserum. Brain pain medications in the treatment of CLBP patients, most have indeed reported improved pain control. However, the evidence 15. Kaplan H, Fields HL. Hyperalgesia during acute opioid abstinence of improved function in daily activities was limited.3-7 More- for a nociceptive facilitating function of the rostral ventromedial over, in a systematic review of its efficacy, Kalso and colleagues8 medulla. J Neurosci. 1991;11(5):1433-1439.
conclude that there are few controlled studies at this time which 16. Bederson JB, Barbaron M, Fields HL. Hyperalgesia following naloxone-precipitatedwithdrawal from morphine is associated definitively support the efficacy of opioids as a monotherapy with increased on-cell activity in the rostral ventromedial medulla. in the management of chronic nonmalignant pain.9 This is Somatosens Mot Res. 1990;7(2):185-203.
where a more comprehensive treatment program such as that 17. The use of opioids for the treatment of chronic pain. A consensus presented by Dr. Hartigan becomes an essential component statement from the American Academy of Pain Medicine and the of overall comprehensive biopsychosocial pain management. American Pain Society. Clin J Pain. 1997;13(1): 6-8. Indeed, the interdisciplinary functional restoration approach 18. Rainville J, Hartigan C, Martinez E, et al. Exercise as a treatment originally pioneered by Mayer and Gatchel10,11 has unequivo- for chronic low back pain. Spine J. 2004;106-115.
19. Brox JI, Reikeras O, Nygaard O, et al. Lumbar instrumented fu- cally documented this.
sion compared with cognitive intervention and exercises in patients Finally, one last point should be noted concerning the use with chronic back pain after previous surgery for disc herniation: of LTOAT. Today, many physicians are still reluctant to utilize a prospective randomized study. Pain. 2006;122:145-155.
opioids for chronic pain patients, often questioning long-term 20. Fairbank J, Frost H, Wilson-MacDonald J, et al. Randomized effectiveness and voicing concerns of fostering addiction. Rec- controlled trial to compare surgical stabilization of the lumbar ognizing this concern, a Task Force of the College on Problems spine with an intensive rehabilitation program for patients with of Drug Dependence authored a position paper in 2003 citing chronic low back pain: The MRC spine stabilization trial. BMJ. "…the need to strike a balance between risk management strate- gies to prevent and deter prescription opioid abuse and the need for physicians and patients to have appropriate access to opioid Dr. Gatchel's Comments
pharmaceuticals for the treatment of pain."12 To achieve this, the Both commentators make a very strong case based upon clinical Task Force highlighted the necessity of comprehensive assess- research for their respective positions. On the one hand, Dr. ment of opioid use and potential risk of opioid misuse/abuse in Schofferman presents compelling evidence for the potential ef- pain patients. As a result, clinical investigators started to develop ficacy of LTOAT for many patients who have intractable CLBP. and validate relevant criteria and screening instruments for as- On the other hand, Dr. Hartigan makes an equally compelling sessing the risk for opioid misuse in chronic pain patients. For case for an intensive exercise-based/cognitive behavioral ap- example, Gatchel and colleagues9,13 have developed the Pain proach. However, after reading these two excellent commentar- Medication Questionnaire (PMQ), a brief, 26-item self-report ies, my immediate reaction was why should there be an either/or screening instrument for potential opioid misuse. As Passik and type of decision as to which is the best approach? In keeping Kirsh14 have noted concerning our work in this area, they con- with the true essence of a biopsychosocial interdisciplinary ap- clude that we "…should be congratulated for completing some proach to CLBP management, multiple treatment modalities difficult and elegant work in this area. Clinicians should look should always be considered in helping to maximize treatment to this measure and others, and think about incorporating one gains. It is important to individually tailor treatment programs or more (or experimenting with them) into their documenta- that are matched to a particular patient's needs.1 We now fortu- tion. At the end of the day, a high score on a PMQ is much like nately have a broad range of pain management techniques in our detecting an aberrant behavior in the course of pain therapy. It treatment armamentarium to help tailor the specific treatment is not a ‘red flag' that suggests pain management should grind needs for specific patients. This is the real strength of such an to a halt. Rather, it is a ‘yellow flag'—a caution sign that merits interdisciplinary approach—to move away from a unimodal- thoughtful consideration and careful management."14 Indeed, treatment type of thinking.
careful assessment and monitoring of patients before, during We are all aware of the statistics concerning the economic and after a pain management treatment program should be a costs of low back pain. An estimated 17.6% (22.4 million) of all cardinal rule of all health care providers.
workers in the US lost time from work because of back pain.2 In conclusion, the heuristic value of a biopsychosocial ap- Moreover, greater than 75% of all low back pain costs are in- proach to chronic pain management is that it does not force curred by 10% of claimants who remain disabled for greater one to make an either/or type of decision as elaborated by Drs. than six months.3 Finally, the cost of low back pain compensa- Hartigan and Schofferman. Fortunately, with the growing ar- November/December 2006 mamentarium of pain management techniques at our disposal, we are not limited only to monotherapy. In this present clinical case of chronic intractable pain, for example, a comprehensive in- terdisciplinary program can be tailored for this patient in which pain symptomatology can be addressed with appropriately monitored LTOAT, along with other biopsychosocial treatment components such as functional conditioning, acquisition of more effective pain coping skills, etc.
"To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science." –Albert Einstein 1. Gatchel RJ. Clinical Essentials of Pain Management. Washington, DC: American Psychological Association; 2005.
2. Guo HR, Tanaka S, Halperin WE, Cameron LL. Back pain preva- lence in US industry and estimates of lost workdays. Am J Public 3. Hale ME, Fleischmann R, Salzman R, et al. Efficacy and safety of controlled-release versus immediate-release oxycodone: Random- ized, double-blind evaluation in patients with chronic back pain. Clin J Pain. 1999;15:179-183.
4. Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine. 1998;23:2591-2600.
5. Cherkin DC, Wheeler KJ, Barlow W, Deyo RA. Medication use for low back pain in primary care. Spine. 1998;23:607-614.
6. Salzman RT, Roberts MS, Wild J, Fabian C, Reder RF, Goldenheim PD. Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control? J Pain Symptom Manage. 1999;8:271-279.
7. Schofferman J. Long-term opioid analgesic therapy for severe refractory lumbar spine pain. Clin J Pain. 1999;15:136-140.
8. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. schner M, et al. Development of a self-report screening instrument 9. Holmes CP, Gatchel RJ, Adams LL, et al. An opioid screening for assessing potential opioid medication misuse in chronic pain instrument: long-term evaluation of the utility of the pain medica- patients. J Pain Symptom Manage. 2004;27:440-459.
tion questionnaire. Pain Practice. 2006;6:74-88.
14. Passik SD, Kirsh KL. Fear and loathing in the pain clinic. Pain 10. Mayer TG, Gatchel RJ. Functional Restoration for Spinal Disorders: Medicine. 2006;7:363-364; discussion 5-6.
The Sports Medicine Approach. Philadelphia: Lea & Febiger, 1988.
11. Mayer TG, Gatchel RJ, Mayer H, Kishino ND, Keeley J, Mooney VA. A prospective two year study of functional restoration in Author Disclosures
industrial low back injury utilizing objective assessment. JAMA. n J Schofferman: nothing personal to disclose. However, our practice receives financial support from commercial sources for fellowship 12. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. training, invests in a surgery center and a device manufacturer, and College on Problems of Drug Dependence task force on prescrip- accepts lunches from pharmaceutical companies which result in the tion opioid non-medical use and abuse: position statement. Drug following financial disclosures: k-3 & m-3, Medtronic Sofamor Alcohol Depend. 2003;69:215-232.
Danek & Depuy.
13. Adams LL, Gatchel RJ, Robinson RC, Polatin PP, Gajraj N, De- n C Hartigan: nothing to disclose.
Direct or indirect remuneration: a. royalties. b. stock ownership (options, warrants). c. consulting fees. d. loans from the sponsor. e. speaking arrangements. Position held in a company: f. board of directors. g. scientific advisory board. h. other office in a company. Support received from sponsors: i. endowments. j. research support for investigator salary. k. research support for staff and materials. l. discretionary funds. m. support of clinical staff or training. n. trips/travel. o. other sponsorship. Degree of Support: 1. less than $250 per year. 2. $250 up to $10,000 total support (from all sources combined) per year, or less than or equal to 5% company ownership if value of ownership is less than or equal to $10,000. 3. more than $10,000 total support (from all sources combined) per year, or more than 5% company ownership.
Part Number: 17152357-1 Version 7 Ventis™ MX4 Product Manual Table of Contents COPYRIGHT NOTICE . 3 WARNINGS AND CAUTIONARY STATEMENTS . 3 General . 3 Personnel . 3 Hazardous Conditions, Poisons, and Contaminants . 3 Factors that Affect Monitor Performance . 4 Certifications . 4 Recommended Practices . 4
LEY DE LA JURISDICCION CONTENCIOSO ADMINISTRATIVA Ley 35 Registro Oficial 338 de 18-mar-1968 Ultima modificación: 10-feb-2014 Estado: Vigente NOTA GENERAL: El Código Orgánico Integral Penal entrará en vigencia en ciento ochenta días contados a partir de su publicación en el Registro Oficial, dado por Ley No. 00, publicada en Registro Oficial Suplemento 180 de 10 de Febrero del 2014 , el mismo que derogará los artículos 11, 13, 13A, 14, 16 y 17 de la presente Ley. LA COMISION LEGISLATIVA PERMANENTE, En ejercicio de sus atribuciones, y por haber recibido dictamen favorable de la Comisión Auxiliar de Legislación Administrativa, expide la siguiente: LEY DE LA JURISDICCION CONTENCIOSO - ADMINISTRATIVA CAPITULO I Del Ejercicio de la Jurisdicción Contencioso - Administrativa Art. 1.- El recurso contencioso - administrativo puede interponerse por las personas naturales o jurídicas contra los reglamentos, actos y resoluciones de la Administración Pública o de las personas jurídicas semipúblicas, que causen estado, y vulneren un derecho o interés directo del demandante. Jurisprudencia: