Pain Pump Law Blog : Medical Device and Malpractice Lawyer & Attorney for Local Anesthetic Infusion Pump & Post-Operative Infection Cases

I have been reviewing the FDA's regulatory scheme over pain pumps and believe I've identified several  weaknesses which are likely to adversely affect patient safety.

Pursuant to 21 United States Code 360c, medical devices are divided into three classes for purposes of regulation: Class I, General Controls; Class II, Special Controls; and Class III, Pre-Market Approval.

The pre-market approval process is rigorous and the FDA requires a device manufacturer to submit considerable documentation regarding a device’s safety and effectiveness in order to obtain approval. Understandably, device manufacturers prefer to attempt to have their devices approved as Class I or II devices.

I was surprised to find that Class III is actually the default classification. Subsection (f) of 21 USC 360c provides:

Any device intended for human use which was not introduced or delivered for introduction into interstate commerce or commercial distribution before May 28, 1976, is classified in Class III unless—

(A) The device—

(i) is within a type of device (I) which was introduced or delivered for introduction into interstate commerce for commercial distribution before such date and which is to be classified pursuant to subsection (b) of this section or (II) which was not so introduced or delivered before such date and has been classified in Class I or II, and

(ii) is substantially equivalent to another device within such type…(emphasis added)

Pain pumps are classified as Class II devices pursuant to federal regulation 21 CFR 880.5725, which covers infusion pumps and is part of the overall regulation of general hospital and personal use devices.  Class II devices are subject to special controls and for pain pumps this concerns performance standards.  A pain pump manufacturer is required to certify in its application materials to the FDA that its device meets an industry standard relating to infusion pumps.  These standards include:  1) AAMI (Association for the Advancement of Medical Instrumentation),  Draft Infusion Device Standard; 2) UL (Underwriters Laboratory) 544 Standards for safety, medical and dental equipment; and 3) IEC (International Electrotechnical Commission) 601-1/ANSI (American National Standards Institute) ES1-1985 Safe Current Limits for Electromedical Apparatus. 

I'm sure these standards are important and applicable to the safe-functioning of many types of infusion pumps. I'm also sure they're relevant to the types of adverse events in infusion pumps the FDA recently announced it was seeking to combat through tighter regulation.  (My post on this is here ).  However, most pain pumps are much less mechanically-complicated than the infusion pumps used to deliver insulin or chemotherapy drugs (to name a few types).  So, these standards really don't get at the main safety concerns with pain pumps which involve the basic threshold question of whether they are reasonably safe for their intended use of continuous infusion of local anesthetics.  As a result, I don't see the FDA's classification of pain pumps as Class II devices conferring any benefits for patient safety.

To my knowledge, all pain pump manufacturers have received approval from the FDA by utilizing the substantial equivalence provision mentioned above.  In this process, the FDA requires device manufacturers to submit a Section 510(k) Pre-Market Notification of intent to market the device. If approved, the FDA issues a letter (see example here) with the following operative language: “The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.”

In March 1993, the FDA issued Guidance on the content of Pre-Market Notification [510(k)] Submissions for external infusion pumps. Section II D is on device description. The description is required to provide a clear statement of the intended use(s) of the infusion pump, including specifying the route(s) of administration and if the infusion pump is labeled for use with a specific drug/biologic the applicant must supply information demonstrating that use of the drug/biologic with the device is consistent with the approved drug/biologic labeling.

Pain pumps are clearly labeled for use with local anesthetics. However, as I have argued in a previous post, the continuous infusion provided by pain pumps is not an approved use of local anesthetics, especially the most commonly used—Marcaine.

For example, in its 1998 510(k) submission for its PainBuster pump, I-Flow reported that there are no specific drugs referenced in the labeling for the PainBuster infusion system, but that it is intended for use with general local anesthetics. I suspect that most, if not all, 510(k) submissions for pain pumps list only a similar general statement.

The FDA could insist that pain pump manufacturers provide evidence in their 510(k) submissions demonstrating how these devices are consistent with the uses approved in local anesthetic labeling. Manufacturers would then be forced into attempting to characterize the use of local anesthetics in their devices--continuous infusion--as akin either to local infiltration or a peripheral nerve block (PNB), which are approved uses. 

Local infiltration involves the injection of a small amount of local anesthetic, typically near a surgical site. Far too much anesthetic is delivered by a pain pump for a manufacturer to claim it is similar to local infiltration.

A PNB likely utilizes a larger amount of anesthetic than in local infiltration, but typically does not approach the volume used in a pain pump. Also, a PNB involves the insertion of a catheter at some distance from an incision site, while a pain pump catheter is intended to be inserted close to an incision. Traditionally, PNBs were accomplished with a single dose of local anesthetic. However, in recent years continuous PNBs have begun to be used by anesthesiologists. Dr. Brian Ilfeld is one of the leading researchers on this technique; here's an article by him on PNBs

It is unclear to me whether continuous PNBs are really an approved use of local anesthetics, per the manufacturers' labeling. However, the articles I’ve seen indicate a greater degree of safety than with pain pumps. I would think this has much to do with continuous PNBs being performed by anesthesiologists as opposed to pain pumps which are typically placed by surgeons. A catheter which will deliver a local anesthetic at a greater distance from a surgical site is less likely to produce wound healing problems. Also, an anesthesiologist is likely to pay closer attention to the volume of local anesthetic used in a continuous PNB than a surgeon utilizing a pain pump.

The incidence of adverse events involving pain pumps has certainly been such that much greater regulatory scrutiny is warranted. These events extend far beyond chondrolysis in shoulder surgeries.  (See my prior post).  The FDA's recently announced requirements that pain pump manufacturers and local anesthetic manufacturers must revise their product labels to highlight the risk of chondrolysis in shoulder surgeries leaves unaddressed the more basic question of whether continuous infusion is a safe use.  The FDA should require pain pump manufacturers to provide detailed evidence about why their devices are consistent with the uses approved by local anesthetic manufacturers. 
 

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In my last post, I discussed a 2008 research article which found a relationship (in both duration of exposure and concentration) between Bupivacaine and muscle damage.   In a prior post, I sought to summarize some earlier articles which also discuss local anesthetics and myotoxicity.  Given the significant evidence that seems to support this troubling relationship, I've wondered if there are any efforts to develop alternatives to existing local anesthetics, especially Bupivacaine.

In "Prolonged Duration Local Anesthesia With Minimal Toxicity," (2009) Hila Epstein-Barash and colleagues (which include Dr. Daniel S. Kohane, one of the authors of the above 2008 article) describe a compound which has powerful anesthetic properties but with causes little damage to human cells.  The authors explain the motivation behind their research:

The development of local anesthetics to provide prolonged analgesia from a single injection has encountered 3 principal challenges: inadequate duration of action, systemic toxicity, and adverse local tissue reaction. The purpose of this research was to produce a local anesthetic lasting many days without those detrimental sequelae.

Conventional local anesthetics are intrinsically myotoxic. They are also myotoxic when released from a wide range of delivery systems, even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure, suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds. (citations omitted)

The article is quite technical and I don't begin to understand all of its complexities.  What I do grasp, however, is that the researchers developed a formulation called STX (saxitoxin) which is a site 1 sodium-channel blocker, which blocks nerves in a different manner than conventional local anesthetics.  Site 1 sodium channel blockers are known not to cause myo- or neuro-toxicity.  The authors were interested in providing a controlled release of STX over an extended period of time in order to attempt a prolonged nerve block, so they used liposomes--tiny bubbles made of the same material as cell membranes--as a delivery vehicle for the medication.  The authors reported that in cell cultures of rats, Bupivacaine but not STX was myo- and neuro-toxic in both time and concentration dependent manners.  The authors state these results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

I have no idea how far in the future STX might be approved and available for human use.  However, it is encouraging to know that there are scientists concerned enough about the shortcomings of Bupivacaine and other conventional local anesthetics who are working to create safer alternatives. 

 

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In a recent article entitled, Local Myotoxicity from Sustained Release of Bupivacaine from Microparticles, Padera, et.al., state:

Myotoxicity is a well-recognized side effect of local anesthetic administration, perhaps particularly of extended exposure, whether from controlled-release methodologies or from catheter-related methods. Occasionally, the consequences can be clinically significant.

These authors studied a variety of controlled-release systems designed to prolong the duration of local anesthetics. The authors gave rats sciatic nerve blocks by injecting them with different bupivacaine solutions and found muscle damage in all of the animals, with greater damage from the encapsulated (higher concentrated) bupivacaine particles than from free bupivacaine (the 0.5% bupivacaine hydrochloride solution commonly used in surgeries). Local anesthetic-induced myotoxicity generally recovers rapidly, often within two weeks, however, the authors noted some controlled-release formulations cause myotoxicity at least as far out as one month after injection.

One possible explanation of this observation is that local anesthetic myotoxicity is time-dependent. Myotoxicity was found to increase with the concentration of bupivacaine, but also markedly with duration of exposure. For example, 62 +/- 12% of cells exposed to 0.025% bupivacaine survived a 2-hour exposure, whereas only 1 +/- 2% survived at 3 weeks. It is important to note that this is an extremely weak concentration of bupivacaine: twenty times weaker than 0.5%. The authors go on to say:

This finding raises the possibility that myotoxicity could be an inevitable concomitant of long-term exposure to conventional (amino-amide and amino-ester) local anesthetics, irrespective of the technology used to deliver them. Myotoxicity is a well-known occurrence in clinical or investigational use of conventional local anesthetics. Although it can have severe consequences, it has not generated much clinical concern. In fact, intramuscular local anesthetic injection is a standard treatment for trigger points in myofascial pain syndromes, and local anesthetic myotoxicity is generally reversible. The distinction that must be made, however, is that those treatments generally involve a single-shot drug injection with a brief duration, whereas microparticulate systems can result in very high local concentrations and/or weeks of local anesthetic exposures.

The findings of this article raise alarming concerns about pain pumps. The continuous repeated exposure to tissues (especially around a healing surgical wound) with local anesthetics (known to cause cell damage and even death) over a period of 48 to 120 hours seems much more likely to result in cell damage than if the same volume of the medication was injected at a single time.

The potential for irreversible cell damage—necrosis—caused by local anesthetics and infusion pumps seems site-dependent. Pain pump manufacturers have acknowledged as much. I-Flow, in its current Directions For Use for the On-Q pump states:

To avoid complications in restrictive spaces use the lowest flow rate, volume and drug concentration required to produce the desired result. In particular:

Avoid placing the catheter in the distal end of extremities (such as nose, ears, fingers, groin area, penis, toes, etc.) where fluid may build up as this may lead to ischemic injury or necrosis.

However, this warning (also contained in I-Flow’s Technical Bulletin on hand and foot surgery) is too limited in scope. While it would apply to bunionectomies, it does not apply to any other foot or ankle surgeries, including catheter placements in the top of the foot near the ankle. This is certainly a restrictive space, made even more so when it is under a compression dressing following surgery. Two pain pump cases I have involve foot surgeries with catheter placements in this location, with disastrous complications to the patients.

The more often I read about the toxicity of local anesthetics, especially bupivacaine, the more I suspect it routinely causes damage to the patient (maybe always causes damage), but that harm is often not detected because the affected cells regenerate or scarring or other damage occurs which may not manifest itself until far in the future. Even when the damage arises to visible injury, many of these injuries are not properly diagnosed as local anesthetic tissue toxicity, but rather as post-operative infections. This is what occurred in the two foot surgery cases I mentioned above.

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I am still a bit confused as to whether the new oversight regime the FDA announced yesterday applies to the disposable local anesthetic infusion surgically-implanted pumps that are my focus in this blog.

Reading the New York Times article on the announcement led me to think these devices might be excluded, as it focuses on IV-implanted, programmable devices used to provide insulin, chemotherapy, and pain medications (but patient-controlled).  There have been over 56,000 adverse events and 710 deaths involving these devices in the past 5 years.  These are truly staggering numbers.  Regarding the types of problems reported, the FDA Press Release indicates: The most common types of reported problems have been related to:

* software defects, including failures of built-in safety alarms;
* user interface issues, such as ambiguous on-screen instructions that lead to dosing errors; and
* mechanical or electrical failures, including components that break under routine use, premature battery failures, and sparks or pump fires.

Failures of infusion pumps have been observed across multiple manufacturers and pump types. The FDA says that many of the reported problems appear to be related to deficiencies in device design and engineering.

I saw nothing about shoulder chondrolysis or other injuries from local anesthetics. So far, all of this sure seemed outside the scope of pain pumps. 

The next step up in document complexity is the FDA's White Paper on its Infusion Pump Improvement Initiative.   I read  "In general, an infusion pump is operated by a trained user, who programs the rate and duration of fluid delivery through a built-in software interface" and it confirms my initial belief.   However, then among the pump mechanisms elastomeric is listed and this is one of the most common types for disposable pain pumps.  Finally, at the end of the paper I see among the footnotes:  1 This document does not pertain to implanted infusion pumps, which are surgically placed in the body.  Okay, now I'm pretty sure this significant announcement doesn't apply to the devices with which I'm familiar.  However, there are several additional documents the FDA has included and, for completeness sake, I read on.

The letter to infusion pump manufacturers from Jeffrey E. Shuren, Director of the FDA's Center for Devices and Radiological Health (CDRH) also focuses on software, design, human factors, and manufacturing problems. 

There's detailed information about CDRH's software research on infusion pumps.  I had no idea the FDA has a software engineering laboratory. 

Ultimately, there's the agency's Guidance for Industry and Staff regarding 510(k) Pre-Market Notification Submissions.  This is a draft document (34 pages in PDF form) which will be entering a 90-day comment period.  When complete it will replace the Guidance on the Content of Premarket Notification [510(k)] Submissions for External Infusion Pumps, issued March, 1993.  

My confusion was finally resolved (I think) by reading the Scope section of this document.  It makes clear that all infusion pumps addressed by 21 C.F.R. 880.5725 will be covered by the new guidelines. This includes numerous types of devices including all Elastomeric Infusion Pumps (products coded MEB), and excludes only the following: gallstone dissolution pumps (MHD), opthalmic infusion pumps (MRH), and analytical sampling infusion pumps (LZF).   Just to be sure, I double-checked the most recent 510(k) Submission for the On-Q Painbuster, which confirms the same regulation (880.5725) and product code (MEB). 

So, it does indeed look like I-Flow, Stryker and company will have to learn how to comply with considerable new requirements and provide alot of additional information in future premarket submissions to the FDA.   This is certainly good news, but I have lingering confusion because of the lack of mention in any of these new documents from the FDA of the adverse events involving these devices with which I'm familiar.   An Appendix to the Guidance document lists the following categories of "Risks to Health" with infusion pumps:  Overdose, Underdose, Delay in Therapy, Incorrect Therapy (wrong medication or correct medication but wrong dosage or infusion rate), Air Embolism, Trauma (burns, cuts, abrasions, bruising), Electric Shock, Infection, Allergic Response, and Exsanguanation.  Perhaps the numerous cases of chondroylsis and tissue necrosis are intended to be included in one of these categories (Infection? Allergic Response?). 

When I think again about the number of adverse events--56,000--reported involving all types of infusion pumps over just the last 5 years, I realize that the number involving local anesthetics, even if it's 500 or more, is likely to be less than 1% of the overall events.  Where do local anesthetic infusion pumps and the injuries they appear to cause fit into the broader regulatory and safety scheme involving this class of devices?  My initial reaction is that the problems with pain pumps don't have much to do with design, human factors, or manufacturing issues (and certainly not software).    I will certainly reserve judgment and keep an eye on how the new oversight regime takes shape.  Of course, it will also be interesting to see how these developments may affect litigation involving injuries and deaths from PCA and other programmable pumps.  I can envision claims which were initially viewed as malpractice expanded to also (or instead) focus on the liability of the pump manufacturer. 

 

 

 

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I recently came across a post by Armand Rosetti which summarized some news articles relating to I-Flow Corporation and its Chief Executive, Donald Earhart. Especially interesting are some statements Mr. Earhart made in a November 5, 2008 conference call with investment analysts regarding the company’s third quarter earnings.  Earhart was answering questions regarding the status of the shoulder chondrolysis lawsuits, and said:

I’ve said this argument before on the conference calls, is that a pain pump or a delivery device, whether it be a syringe or one of our pumps delivering a drug, how do you blame the device, because there’s no way the device can cause the disappearance of cartilage. It would have to be whatever is delivered into the site or would have to be the technique by the doctor or would have to be the sutures or it would have to be the staples or it would have to be something else used during the surgery, but it can’t be our pump, because our pump can’t cause cartilage to disappear…. It’s like using a syringe to deliver a narcotic. We can’t be held responsible for the side effects, if I’m the syringe manufacturer, of the drug.

This raises an important point.  Clearly, it is the toxicity of the local anesthetic that causes the direct harm to the patient--whether the result be the destruction of shoulder or other joint cartilage, tissue necrosis around a surgical site, or other injury.  How then can a plaintiff reasonably seek to blame the maker of the device and not the drug?  Because a pain pump manufacturer retains a legal responsibility to patients to provide that their devices may be safely used with local anesthetics in a manner intended by the manufacturer of the local anesthetic.  Continuous infusion through a pain pump is not a listed intended use of a local anesthetic; it is an off-label use.   A statement such as I-Flow makes in its current Directions for Use for the On-Q pump, “medications or fluids must be administered per instructions provided by the drug manufacturer,” has little meaning when the use in question is not addressed by the manufacturer. 

Mr. Earhart and I-Flow appear to take for granted that continuous infusion is no different than the uses approved by the local anesthetics manufacturers. I contend pain pumps represent a categorically different use both because of the larger volume of local anesthetic infused and the significantly greater duration of exposure of the affected tissues to the medication. For example, a single bolus dose of 100 mg (20 ml) of Marcaine to produce a nerve block may well create less risk of local tissue toxicity than continuously infusing smaller volumes—2ml/hr—but with a larger total volume 240 mg (100 ml) over a much longer time—2-5 days.

On the other hand, the uses to which a syringe is put--—local infiltration around a surgery site and injections to produce various types of nerve blocks—are approved uses by the drug manufacturer.  Because there are a variety of known risks of patient injury with their devices, pain pump manufacturers have a duty  to timely and adequately convey warnings of such risks to the physicians who use them. 

 

 

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A number of articles have reported a relationship between local anesthetics and myotoxicity—damage to muscle; for example: Zink, et.al. (2004), Zink, et.al. (2003), Irwin et.al., (2002), Nonaka, et.al. (1983). Published before the widespread use of pain pumps, a 1994 article by Hogan, et.al., begins with the following accepted generalizations:

All local anesthetics that have been tested are myotoxic. Procaine produces the least and bupivacaine the most severe injury. Injection of local anesthetics intramuscularly or into adjacent subcutaneous tissue results in myonecrosis. The extent of muscle injury from local anesthetics is dose dependent and worsens with serial administration.

Local anesthetics are injected into muscle for treatment of myofascial pain, in wound margins during surgery, and for neural blockage during surgical anesthesia.

The authors describe a female patient who underwent capsular release of the left shoulder. Because continuous passive shoulder motion and physical therapy were planned immediately following the surgery, a nerve block during and after the procedure was planned. A catheter was placed in the left interscalene groove at the level of the cricoid cartilage. Bupivacaine (0.5%) with epinephrine was injected incrementally to a total volume of 45 ml (200mg), producing sensory and motor blockade of the shoulder, arm, and hand.

When the woman began experiencing shoulder pain approximately 16 hours post-operatively, she received additional bolus doses of the 0.5% bupivacaine with epinephrine through the catheter. The doctors used additional injections of the same solution through the catheter when the woman’s shoulder pain did not resolve. After 34 hours, the catheter was removed. The total dose was 228 ml (1140 mg). The woman developed persistent pain in the left side of her neck. Imaging was suggestive of a tissue injury.  Approximately 8 weeks post-op, a muscle biopsy  showed injury to the muscle fibers.

Large doses of bupivacaine were used on the patient because of the authors’ desire to provide pain relief suitable for the expected post-operative manipulations of her shoulder. Because the injections failed to produce the desired effect, they suspected the catheter tip became dislodged.

According to the authors, while myotoxicity of local anesthetics has been widely produced in experimental settings, reports in human patients are uncommon. The authors’ next observations are why this article is interesting regarding pain pumps:

Local anesthetic injection for neural blocks only occasionally requires intramuscular injections of large volumes…. These are not usually repeated, and the injection site is difficult to examine. Small volumes are used with injections for intercostal, supraspinatus or musculocutaneous nerve blocks and with trigger point injections and stellate ganglion blocks.

Because experimental studies show myonecrosis after single injections of even minimal doses of local anesthetic, it is likely that myopathy occurs after most injections but is not recognized because of rapid and complete recovery.

Local pain for which trigger point injections are performed may disguise myopathic changes, and discomfort and dysfunction after injections performed for surgical anesthesia can be readily attributed to surgery or concealed by surgical pain. Splinting prevents tenderness from being identified. The pain of inflammation develops only after 3 or 4 days, and the appearance of atrophy takes longer; thus, these events frequently may be missed or not correlated to the administration of anesthetic agents. (My emphases)

Caveats: this 1994 article pre-dates the widespread use of pain pumps.  The authors utilized Bupivacaine (0.5%) with epinephrine. Several years ago, pain pump manufacturers began recommending against using local anesthetics with epinephrine. Further, the large volume of Bupivacaine injected into the woman’s shoulder undoubtedly exceeded the manufacturer of Bupivacaine’s maximum recommended dose of 400 mg within a 24-hour period. In light of the numerous recent reports of chondrolysis, the fact that such a large volume of Bupivacaine with epinephrine was injected into the woman’s shoulder near cartilage is alarming (although the authors seem to believe that the catheter had become dislodged from its original location).

Nonetheless, the article raises a number of concerns regarding continuously infused local anesthetics and pain pumps.  As the authors’ comments make clear, at the time this article was written, local anesthetics were typically used in relatively small amounts around the surgical site and to produce nerve blocks.   Even small amounts, however, routinely cause cells to die, but they typically regenerate without incident. Post-operative pain and inflammation often mask symptoms that may actually be associated with damage to tissues.

In small amounts, given the beneficial pain relief afforded by local anesthetics, the temporary harm they cause would seem to be an acceptable side effect.  What happens, though, when these drugs are continuously infused, in or near an open wound, in total volumes larger than commonly used in the past?   There must be factors that cause the usually temporary harm to tissues to take the form of more visible and potentially permanent complications such as wound dehiscence, blistering, sloughing, and necrosis.  These would seem to include:

• Local anesthetic volume
• Local anesthetic concentration
• Rate of infusion
• Duration of infusion
• Surgery/catheter site
• Patient-specific factors-age, weight, risk-factors

The pain pump and local anesthetic manufacturers have failed to properly considered these factors and, instead, make blanket, one-size fits all recommendations to surgeons. 

A bigger question:  Why is the medical community still so routinely using higher concentrations of Bupivacaine when it is known to cause damage to a variety of human cells-- cartilage, muscle, nerve, renal, and undoubtedly others?

 

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On February 19, the FDA approved a revised label for Marcaine (Bupivacaine Hydrochloride), manufactured by Hospira.  The label contains the following warning regarding the risk of chondrolysis:

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

This language generally seems appropriate to me, however, I fail to understand why the FDA permitted the following sentence, "There is insufficient information to determine whether shorter infusion periods are not associated with these findings."  This seems to be an ill-advised attempt by Hospira to create ambiguity about the safety of intra-articular infusion.   The FDA Alert which prompted this warning goes out of its way to note that intra-articular injections of local anesthetics in orthopedic procedures have been given for years without reported incidents of chondrolysis.  The FDA then flatly states:  Neither local anesthetics nor infusion devices are approved for an indication of continuous intra-articular infusion.

The revised Marcaine label also has the following language: 

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. MARCAINE is not approved for this use.

Since the drug is not approved for this use, without regard to the duration of the infusion, why permit the slightest hint of confusion to remain in the label? Especially in light of the research of Constance R. Chu, M.D. that exposures even as short as 30 minutes cause massive death in cartilage cells. 

 

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In my last post, I noted the following language in the FDA's November 13, 2009 warning regarding chondrolysis and pain pumps:

Local anesthetics are approved as injections for the production of local or regional anesthesia or analgesia. The approved drug labels for local anesthetics do not include an indication for continuous intra-articular post-operative infusions or use of infusion devices such as elastomeric pumps. The FDA has not cleared any infusion devices with an indication for use in intra-articular infusions of local anesthetics. (emphasis mine)

This is an accurate and important statement:  pain pumps are an off-label use of local anesthetics. 

Someone else, likely on the side of pain pump manufacturers, seems to agree because this language is now missing from an updated version of the FDA Warning, dated February 16, 2010.  The same paragraph now reads:

Local anesthetics are approved as injections for the production of local or regional anesthesia or analgesia. Neither local anesthetics nor infusion devices are approved for an indication of continuous intra-articular infusion.

I gather that since the warning is focused on the association of chondrolysis and pain pumps, the manufacturers either disputed the statement from the FDA that pain pumps are not an approved indication for any use or contended that it was outside the scope of the warning.   The FDA is requiring pain pump manufacturers and, more importantly, local anesthetic manufacturers, to include warnings of the risk of chondrolysis with continuous intra-articular infusion.  It will be especially interesting to see the drug label changes and whether the manufacturers address the risks of continuous infusion in general and not just into joint spaces. 

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On November 13, 2009, the FDA announced it will require pain pump manufacturers and the manufacturers of the local anesthetics used in them to update their product labels to contain a warning about the risk of chondrolysis following continuous infusion with local anesthetics into joint spaces after orthopedic surgery. 

One paragraph of the FDA announcement particularly caught my attention:

Local anesthetics are approved as injections for the production of local or regional anesthesia or analgesia. The approved drug labels for local anesthetics do not include an indication for continuous intra-articular post-operative infusions or use of infusion devices such as elastomeric pumps. The FDA has not cleared any infusion devices with an indication for use in intra-articular infusions of local anesthetics. (emphasis mine)

This statement confirms my contention that continuous infusion via pain pumps is an off-label use of any local anesthetic.  For example, when Hospira in its label for Marcaine (Bupivacaine) makes recommendations for maximum dose volume for particular uses including local infiltration, peripheral nerve blocks, and epidurals, these same recommendations should not be considered applicable to continuous infusion because it is a categorically different use.  

The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient.
Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization
of each case.
These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. (emphasis mine)

It is clear from the focus on single doses that these recommendations contemplate traditional nerve blocks and not continuous infusion.  As I understand it, most nerve blocks are performed using far less than 175 or 225 mg of Marcaine.  Moreover, the concerns regarding dosage at these volumes have been for neuro- and cardiotoxcity; in other words, systemic and not local toxicities.  Pain pumps represent a categorically different use because of the much larger volume of local anesthetics infused and the great duration of exposure the affected tissues have to the mediation —typically at least two days and as long as five days post-operatively.

Nonetheless, I-Flow's dose recommendations for its own products explicitly rely on the 400 mg total daily maximum recommendation for Marcaine as a toxic ceiling below which pain pumps allegedly may safely continuously infuse this medication.  A commonly-used 100 ml 2 ml/hr. pain pump would mean a 24-hour dose of 240 mg (24 hrs x 2 ml x 5 mg/per ml).  On what evidence are pain pump manufacturers relying that this volume of 0.5% Marcaine is safe for continuous infusion following any surgical procedure? 

Given the known toxic properties of Marcaine and other local anesthetics, in my opinion the proper standard for physicians and manufacturers should be:  what are the lowest dose, concentration, and flow rate that will produce the desired analgesic effect?  Pain pump manufacturers have a financial incentive not to frame the use of their produce in these terms, however.  Because they market their products to surgeons as a more effective alternative to oral narcotics, they are inclined to recommend the use of the most potent of the commonly-used anesthetics--Marcaine--at a high concentration--0.5%--and in large volumes.  More on these issues in my next post.  

 

 

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