Nashville’s Amsurg Corp. has agreed to buy the nation’s largest anesthesia services provider for $2.35 billion.

The cash and stock deal for Sheridan Healthcare will see Sheridan investors issued Amsurg shares worth $615 million,Bloomberg reports, but Amsurg could replace with cash a “substantial portion” of the equity consideration.

Amsurg operates 242 ambulatory surgery centers in the U.S. Sheridan employs more than 2,400 physicians and operates in 25 states.

Almost overnight, a powerful new painkiller has become a $100 million business and a hot Wall Street story.

But nearly as quickly, questions are emerging about how the drug is being sold, and to whom.

The drug, Subsys, is a form of fentanyl, a narcotic that is often used when painkillers like morphine fail to provide relief. The product was approved in 2012 for a relatively small number of people — cancer patients — but has since become an outsize moneymaker for the obscure company that makes it, Insys Therapeutics. In the last year, the company’s sales have soared and its share price has jumped nearly 270 percent.

Behind that business success is an unusual marketing machine that may have pushed Subsys far beyond the use envisioned by the Food and Drug Administration. The F.D.A. approved Subsys only for cancer patients who are already using round-the-clock painkillers, and warned that it should be prescribed only by oncologists and pain specialists. But just 1 percent of prescriptions are written by oncologists, according to data provided by Symphony Health, which analyzes drug trends. About half of the prescriptions were written by pain specialists, and a wide range of doctors prescribed the rest, including general practice physicians, neurologists and even dentists and podiatrists.

 

The drug is a narcotic often used when other painkillers don’t provide relief.

Interviews with several former Insys sales representatives suggest the company, based in Chandler, Ariz., has aggressively marketed the painkiller, including to physicians who did not treat many cancer patients and by paying its sales force higher commissions for selling higher doses of the drug.

Under F.D.A. rules, manufacturers may market prescription drugs only for approved uses. But doctors may prescribe drugs as they see fit. Over the last decade, pharmaceutical companies have paid billions of dollars to settle claims that they encouraged doctors to use drugs for nonapproved treatments, or so-called off-label uses, to increase sales and profits.

Drug-safety experts said the range of medical professionals who appeared to be prescribing Subsys was troubling, particularly given concerns about the widespread use — and abuse — of narcotic painkillers. In December, Insys disclosed that it had received a subpoena from the federal health department’s Office of the Inspector General for documents related to its sales and marketing practices. The company has said it is cooperating with the investigation.

Medicine aside, Subsys is, much as anything, a Wall Street story. The explosive growth of Insys was fanned first by Wall Street investors betting the company’s sales and share price would rise. Now, other investors are betting the stock will decline. Over the last week, shares of Insys have lost roughly a third of their value, after the arrest on federal fraud charges of a Michigan neurologist who was a top prescriber of Subsys. In a statement, Insys said it took patient safety seriously and was committed to working with doctors to ensure its products were used properly.

Drug-safety experts said it was crucial that products like Subsys be marketed responsibly because the drugs are powerful, and powerfully addictive.

“You’re essentially spreading the accessibility to a very potent, rapid-onset narcotic to a large number of people, and a number of them may get addicted,” said Dr. Sidney M. Wolfe, founder and senior adviser to the Public Citizen Health Research Group, a consumer organization.

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Oral fentanyl products like Subsys have a history of being broadly prescribed. In 2008, the drug company Cephalon pleaded guilty to a criminal charge and paid $425 million in fines for inappropriate marketing of its products, including Actiq, a fentanyl lollipop, which federal officials said was being promoted for a range of unapproved uses, including treatment of migraines.

In 2007, Cephalon sought approval from the F.D.A. to market a newer fentanyl product, a dissolving pill called Fentora, for use in people without cancer. At the time, F.D.A. officials cited data showing the product was already being widely used by noncancer patients and they later denied the company’s application. Cephalon was acquired by Teva Pharmaceutical Industries in 2011.

Dr. Margaret A. Hamburg, the F.D.A. commissioner, said the agency did not regulate how doctors practice medicine. Still, she acknowledged that the widespread prescribing of oral fentanyl products for off-label uses was troubling, especially given the agency’s efforts to restrict the use of fentanyl and other opioids in the face of painkiller abuse. In the case of products like Subsys, prescribers must undergo training about the drug’s risks, pass a test and register in a national database. Patients must sign an agreement with their doctor before being prescribed the drug.

“It is frustrating, and we are in a process of continually assessing how our approaches are unfolding in the real world,” Dr. Hamburg said.

Several doctors said products like Subsys, which is sprayed under the tongue, fill an important role for seriously ill cancer patients, who may need the drug if their condition worsens or if their standard painkiller regimen occasionally fails to work.

“You want it to work as quickly as possible,” said Dr. Joshua R. Wellington, a pain specialist at Indiana University Health University Hospital. He is a paid speaker for Insys and said he prescribed it only to cancer patients. “In my mind, that’s what sets it apart.”

Still, Subsys has sold surprisingly well given the drug is approved only for cancer pain, and given that only a small number of oncologists, who are typically responsible for treating their patients’ pain, appear to be prescribing it. In addition to pain specialists and anesthesiologists, who together made up about half of all prescriptions, a significant number were written by neurologists and physical medicine and rehabilitation specialists, who often treat patients with a variety of pain conditions.

The former sales employees said that while the company targeted some oncologists, it placed more focus on high prescribers of competing products like Actiq and Fentora, regardless of whether those doctors treated cancer patients. They also said they were trained to mention the restriction to cancer pain at the beginning of the sales pitch and then to move on to a more general discussion of “breakthrough pain” in the doctors’ other patients.

Dr. Wellington said while he did not prescribe the drug off-label, he understood why some colleagues did. “Cancer pain is not a unique pain syndrome,” he said. “Pain is pain.”

Others disagreed.

At least part of Insys’s business strategy appears to rely on the assumption that patients will eventually need more of the drug, along with higher doses. Higher doses are more expensive than lower doses.

Comments from a Wall Street analyst underscore that view. “As Subsys grows more mature, we expect the number of experienced patients to grow,” Michael E. Faerm, an analyst for Wells Fargo, wrote last year in a note to investors. “As the experienced patients titrate higher, the average dose per prescription should increase.”

The former Insys sales representatives said they were paid more for selling higher doses.

Pratap Khedkar, who oversees the pharmaceutical practice at ZS Associates, a global sales and marketing firm, said such a practice was highly unusual because “most companies feel that is the doctor’s decision because it is very patient-specific.”

Many of the sales representatives were new to the pharmaceutical industry and were paid low base salaries, about $40,000 a year, compared with the industry standard of about $80,000, as an added incentive to rack up higher sales commissions, they said. Some said they were told they could make hundreds of thousands by selling aggressively.

Michael L. Babich, the chief executive of Insys, has attributed his company’s sales to its ambitious compensation structure. “We believe this is the most effective way to motivate our sales team,” he told analysts during an earnings call last fall.

On Tuesday, the company reported that Subsys sales continued to grow in the first quarter of this year, to $40.7 million, from $9.7 million a year ago.

Meanwhile, the company’s plans for Subsys are only just getting underway: Earlier this year, Insys announced that it intended to seek approval to market the product for a broader range of uses, including for children and burn patients, and to treat acute pain in emergency rooms.

Anesthesia Management: Ropivacaine plasma levels following local infiltration analgesia for primary total hip arthroplasty

Published in Anaesthesia. 2014 Apr;69(4):368-73

Authors: Gill AM et al. 

Abstract

We measured total and free plasma concentrations of ropivacaine following high-volume, high-dose local infiltration analgesia in 19 patients aged 65 years or over undergoing unilateral total hip arthroplasty. 

The patients received 180 ml ropivacaine 0.2% (360 mg), which was injected into the deep and peri-capsular tissues, the gluteal muscles and fascia lata, and the subcutaneous tissues and skin. 

Patients were monitored for clinical symptoms and signs of systemic local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.081 to 1.707 μg.ml(-1) (mean (SD) 0.953 (0.323) μg.ml(-1) ). Free levels of plasma ropivacaine varied from 0.000 to 0.053 μg.ml(-1) (mean (SD) 0.024 (0.011) μg.ml(-1) ). 

No samples reached the toxic threshold for venous ropivacaine concentration, although four patients exhibited mild symptoms consistent with local anaesthetic toxicity. 

One patient had episodes of complete heart block on ECG monitoring, but plasma ropivacaine levels were below toxic levels. We conclude that plasma levels for ropivacaine associated with toxicity in a volunteer population (total 2.2 μg.ml(-1) , free 0.15 μg.ml(-1) ) are not reached during local infiltration analgesia for hip arthroplasty in elderly patients.

Published in Anaesthesia. 2014 Jun;69(6):550-7

Authors: Glen JB et al   

Abstract

We compared the predictive performance of the existing Diprifusor and Schnider models, used for target-controlled infusion of propofol, with a new modification of the Diprifusor model (White) incorporating age and sex covariates. 

The bias and inaccuracy (precision) of each model were determined using computer simulation to replicate the infusion profiles in an earlier study of 41 patients undergoing surgery with propofol administered by target-controlled infusion and in which timed, measured blood propofol concentrations were available. 

Bias with the White model (5%) was significantly less (p less than 0.0001) than with the Diprifusor (16%) or Schnider (15%) models. The White model showed a significant improvement in accuracy (inaccuracy 19%, p less than 0.0001) relative to the Diprifusor (26%). 

Temporal changes were such that with all three models, bias differed at induction and recovery. None of the models accounted fully for the extent of inter-individual variation in propofol clearance, but the improved performance with the White model suggests it has merit.

 

Published in Can J Anaesth. 2014 Jun;61(6):551-557

Authors: George RB et al.   

PURPOSE:

Acute pain after open abdominal hysterectomy limits the function of patients in the postoperative period, but data regarding the analgesic efficacy of a low dose of pregabalin (75 or 150 mg) have been conflicting. This study was performed to determine if a low dose of pregabalin could decrease postoperative opioid use following abdominal hysterectomy when compared with placebo.

METHODS:

American Society of Anesthesiologists I-II patients older than 18 yr and scheduled for open elective abdominal hysterectomy were recruited for participation and randomized to one of three groups: pregabalin 75 mg (P75), pregabalin 150 mg (P150), or placebo. The study drug was administered two hours prior to surgery and 12 hr following the initial dose. Anesthetic technique and postoperative analgesia were standardized. Postoperative pain was managed using patient-controlled analgesia with morphine. Pain at rest and movement as well as nausea were assessed with an 11-point numeric rating scale.

RESULTS:

One hundred and one patients were recruited, and 89 patients completed the study. Mean (SD) cumulative morphine consumption at 24 hr postoperatively was 54.0 (26.2) mg for the placebo group, 53.1 (22.7) mg for the P75 group, and 44.3 (20.9) mg for the P150 group. Independent Student’s t tests indicated no difference between the placebo group and either the P75 group (95% confidence interval [CI]: -11.75 to 13.44; P = 0.8937) or the P150 group (95% CI: -2.74 to 22.15; P = 0.1238).

CONCLUSIONS:

At the doses used in this study, pregabalin treatment may not be effective in reducing opioid use up to 24 hr postoperatively following abdominal hysterectomy.

 

 

Published in Anaesthesia. 2014 Jun;69(6):583-90

Authors: Wang X et al.   

Abstract

We measured pre-operative hepatic blood flow and postoperative morphine concentration in infants with or without biliary atresia. Thirty-four infants (0-3 months) with biliary atresia undergoing portoenterostomy (Kasai operation) were included and hepatic blood flow was assessed by magnetic resonance imaging before surgery in 12 of them. 

Sixteen subjects (0-3 months) without liver disease undergoing abdominal or pelvic surgery acted as controls and six of them had hepatic blood flow assessed. Intravenous morphine (8 μg.kg(-1) .h(-1) ) was administered to all patients postoperatively. 

The median (IQR [range]) relative hepatic blood flow was 3.51 (2.72-3.88 [1.68-4.43]) with and 3.15 (2.66-4.42 [2.30-5.01]) without biliary atresia (p = 0.851). The median (IQR [range]) morphine concentration after 24 h infusion was 5.9 (4.5-16.4 [2.9-42.2]) ng.ml(-1) and 6.4 (3.2-12.0 [1.9-48.6]) ng.ml(-1) , respectively (p = 0.460). 

An inverse regression relation was found between the morphine concentration and the hepatic perfusion index (R(2)  = 0.519, p = 0.001). Compensatory increases in hepatic arterial blood flow maintain the total hepatic blood flow in infants with biliary atresia.

 

Published in Anaesthesia. 2014 Jun;69(6):558-72

Authors: Lindholm EE et al.  

Abstract

The aim of this study was to define pre-operative echocardiographic data and explore if postoperative indices of cardiac function after open abdominal aortic surgery were affected by the anaesthetic regimen. We hypothesised that volatile anaesthesia would improve indices of cardiac function compared with total intravenous anaesthesia. 

Transthoracic echocardiography was performed pre-operatively in 78 patients randomly assigned to volatile anaesthesia and 76 to total intravenous anaesthesia, and compared with postoperative data. Pre-operatively, 16 patients (10%) had left ventricular ejection fraction less than 46%. In 138 patients with normal left ventricular ejection fraction, 5/8 (62%) with left ventricular dilatation and 41/130 (33%) without left ventricular dilatation had evidence of left ventricular diastolic dysfunction (p less than 0.001). 

Compared with pre-operative findings, significant increases in left ventricular end-diastolic volume, left atrial maximal volume, cardiac output, velocity of early mitral flow and early myocardial relaxation occurred postoperatively (all p less than 0.001). 

The ratio of the velocity of early mitral flow to early myocardial relaxation remained unchanged. There were no significant differences in postoperative echocardiographic findings between patients anaesthetised with volatile anaesthesia or total intravenous anaesthesia. Patients had an iatrogenic surplus of approximately 4.1 l of fluid volume by the first postoperative day. N-terminal prohormone of brain natriuretic peptide increased on the first postoperative day (p less than 0.001) and remained elevated after 30 days (p less than 0.001) in both groups. 

Although postoperative echocardiographic alterations were most likely to be related to increased preload due to a substantial iatrogenic surplus of fluid, a component of peri-operative myocardial ischaemia cannot be excluded. Our hypothesis that volatile anaesthesia improved indices of cardiac function compared with total intravenous anaesthesia could not be verified.

Published in Can J Anaesth. 2014 Apr 25

Authhors: Perez-Protto S et al.

BACKGROUND:

Patients with dementia are thought to be more sensitive to anesthesia, although volatile anesthetic requirement has not specifically been evaluated in this population. We tested the hypothesis that patients with dementia having non-cardiac surgery have a lower ratio of bispectral index (BIS) to minimal alveolar concentration (MAC) during the five minutes immediately preceding incision, thus exhibiting deeper hypnotic levels at a given MAC fraction.

METHODS:

We obtained records from our database registry on patients who had volatile general anesthesia during their most recent operation. We excluded patients premedicated with midazolam. Patients with dementia were identified and their diagnosis was confirmed by chart review. Each patient with dementia was successfully matched with a maximum of five patients without dementia using a multivariate nearest-neighbor distance-matching algorithm restricted to the following criteria: American Society of Anesthesiologists physical status, age, five-minute pre-incision time-weighted average (TWA) estimated effect-site concentration of propofol and fentanyl, and use of remifentanil. Our primary outcome was the TWA BIS-to-MAC ratio during the five minutes immediately preceding incision.

RESULTS:

We analyzed 31 patients with dementia matched with 151 patients without dementia. Median [quartiles] TWA BIS-to-MAC ratios for the matched patients were 85 [73, 100] for the patients with dementia and 78 [73, 84] for the patients without dementia. The percent difference in mean BIS-to-MAC ratios between patients with dementia and patients without dementia was 9% (95% confidence interval: -9% to 29%) (P = 0.35, Wald test).

CONCLUSIONS:

Our results do not support the hypothesis that patients with dementia are more sensitive to volatile anesthetics than patients without dementia.

 

Published in Anaesthesia. 2014 Apr;69(4):348-55

Authors: Niraj G et al,.     

Posterior transversus abdominis plane blocks have been reported to be an effective method of providing analgesia after lower abdominal surgery. We compared the efficacy of a novel technique of providing continuous transversus abdominis plane analgesia with epidural analgesia in patients on an enhanced recovery programme following laparoscopic colorectal surgery. A non-inferiority comparison was used. 

Adult patients undergoing elective laparoscopic colorectal surgery were randomly assigned to receive continuous transversus abdominis plane analgesia (n = 35) vs epidural analgesia (n = 35), in addition to a postoperative analgesic regimen comprising regular paracetamol, regular diclofenac and tramadol as required. 

Sixty-one patients completed the study. The transversus group received four-quadrant transversus abdominis plane blocks and bilateral posterior transversus abdominis plane catheters that were infused with levobupivacaine 0.25% for 48 h. The epidural group received an infusion of bupivacaine and fentanyl. 

The primary outcome measure was visual analogue scale pain score on coughing at 24 h after surgery. We found no significant difference in median (IQR [range]) visual analogue scores during coughing at 24 h between the transversus group 2.5 (1.0-3.0 [0-5.5]) and the epidural group 2.5 (1.0-5.0 [0-6.0]). The one-sided 97.5% CI was a 0.0 (∞-1.0) difference in means, establishing non-inferiority. 

There were no significant differences between the groups for tramadol consumption. Success rate was 28/30 (93%) in the transversus group vs 27/31 (87%) in the epidural group. 

Continuous transversus abdominis plane infusion was non-inferior to epidural infusion in providing analgesia after laparoscopic colorectal surgery.

Retained surgical items after surgery can be a significant source of mortality, morbidity, and cost. Computer-aided detection (CAD) technology can help prevent these costly errors, however, according to a group from the University of Michigan Health System.

By combining a microtag placed on potentially retained foreign objects during surgery with the use of internally developed CAD software to spot these items on radiographs, the researchers believe more than 99% of retained surgical items could be detected.

“The number of cases missed by the CAD and discovered by the radiologist is so small, we anticipate it would be imperceptible during the career of a surgeon,” lead author Dr. Theodore Marentis said.

The researchers presented their experience at the recent SPIE Medical Imaging 2014 conference in San Diego.

Costly errors

Retained surgical items have been associated with approximately 4.5% mortality and 16% permanent disability, and burden the U.S. healthcare system with $1.5 billion a year in entirely preventable expenses, Marentis said.

The reported incidence of retained surgical items ranges between 1 in 1,000 and 1 in 8,000 surgeries, and each incident costs approximately $450,000 in preventable combined medical and legal expenses, he said.

Retained surgical items are “clear-cut cases of negligence, and malpractice caps do not apply,” he said.

Radiographs are commonly used to detect retained surgical items, but they yield less than 60% sensitivity, he said.

“The reason retained surgical items are so often missed even by skilled radiologists, we believe, is because their radiopaque (x-ray visible) elements or filaments are deformable and are not standardized across vendors,” Marentis said. “Their shape changes and creates a perceptual barrier for the radiologist, who may misinterpret the finding as a garment or external to the patient. A large part of the problem is the defective nature of surgical sponges and towels as highly variable detection targets.”

Microtags and CAD

Seeking to improve on this situation, the University of Michigan team developed a method that employs microtags and CAD software. Codeveloped with the Chronis Lab in the university’s bioengineering department, the microtag is visible on radiographs, doesn’t change its shape, avoids high-contrast anatomical features, and produces a similar 2D projection regardless of orientation in space, Marentis said.

CAD software codeveloped with the department of radiology’s CAD Research Laboratory then detects the microtags on radiographs using machine learning techniques. The CAD system includes six task-based processing modules for preprocessing, target enhancement, candidate labeling, segmentation, feature analysis, and classification. Detected tag locations are then highlighted on the radiographs for the radiologist to review.

The CAD software can operate in a “high-specificity” mode for the operating room and point-of-care applications, reducing turnaround time for intraoperative radiographs from 12 to 15 minutes to less than five minutes, he said. It can also run in a “high-sensitivity” mode, allowing the radiologists to identify all retained surgical items while easily discarding false-positive results, Marentis said.

In testing on a large database of cadavers, standalone CAD sensitivity was 93.5% with 0.36 false positives per image in the high-sensitivity mode and 82% with 0.004 false positives per image in the high-specificity mode for operating room use, according to the researchers. With a radiologist reviewing the CAD results, sensitivity reached more than 99%.

“It can eliminate a costly, entirely preventable surgical complication and keep patients safe,” Marentis said.

Failing status quo

Marentis noted that the current clinical practice in 90% of U.S. hospitals to prevent retained surgical items is to perform a surgical count followed by a radiograph if the count is off. However, documented surgical counts were mistakenly thought to be correct in more than 90% of confirmed retained surgical item cases, he said.

“Therefore, the count is not accurate, and a radiograph is never acquired to augment it,” he said. “The clinical status quo fails to address the pressing clinical need.”

Approximately 10% of hospitals have tried to use barcode and radiofrequency technologies to improve detection of retained surgical items, but these require a change of clinical practice and retraining of the operating room staff. The lack of evidence-based outcome data and also the high cost and complexity associated with these approaches have so far prevented wider adoption, Marentis said.

“In contrast, with the proposed approach, a radiograph would be reimbursed $41 by CMS [Centers for Medicare and Medicaid Services], while a surgery costs at least $10,000,” he said. “The cost-benefit analysis of the microtag and CAD combination approach appears quite favorable.”

In the next phase of the group’s work, the team plans to further validate the CAD software in a cadaveric database and with healthy volunteers. They would also like to pilot the technology in an operating and extend the CAD methods to detect other objects, Marentis said.