Pain heads the list of reasons Americans seek medical treatment. Yet those suffering from pain often confront an array of obstacles to pain management. This is all the more reason to find a ray of hope in the bravery and advocacy of Casey Matthews, a 19-year-old Southern California student. Since Casey’s mother has been a victim of chronic pain since his earliest years, the impact of this affliction on his life has been immeasurable. However, the student perceived an opportunity to tackle the trauma in the form of the 2009 National Pain Care Policy Act, S. 660.

The proposed Senate bill would, among other things, identify impediments to successful pain care, assess the efficacy of pain treatment and management, and launch an action agenda for eliminating treatment and upgrading training. (Companion legislation, H.R. 756, passed the House of Representatives in late March.) In completing a political science assignment, Casey produced a video in support of the above measures. He is also delivering to the Senate a petition calling for urgent national action to combat pain and thereby improve the quality of life for millions of Americans. (To see the video or sign the petition, visit the American Pain Foundation at www.painfoundation.org/.) I strongly urge you to sign Casey’s petition; such expressions of collective support for attacking the problem of pain are of vital importance at a time when the debate over reform of the U.S. health care system is once more taking center stage.

I recently represented the sterile compounding pharmacy industry at the Alliance for Patient Access (AfPA) Policy Forum on this issue. My sincere appreciation goes out to the AfPA for planning and executing the meeting and to Drs. David Kloth (Connecticut Pain Care) and Joshua Prager (Center for Rehabilitation of Pain Syndromes and California Pain Medicine Centers) for their leadership on this issue.

Over the course of the two-day forum, leading physicians in pain management and Medicare policy experts (who are also schooled in the detail and history of payment and coverage regulation), discussed the merits of taking a legislative path and negotiating through the coverage, coding and payment web.

Attorneys Paul Radensky and Paul Rudolf of the Arnold & Porter Washington, D.C. office are working with the group in three key areas: drug payment, administrative hassles, and pump refill and electronic analysis/programming code valuation.

The current objectives are:

Drug payment: Seek the development of a fee schedule to replace invoice-based pricing with fair payment to reflect costs for acquiring, handling and maintaining drugs. Pursuing regional fee schedules is a near-term objective under consideration, while longer-term, seeking CMS adoption of a national method for a fee schedule is being examined by the group.

Administrative hassles: Address significant cost and time issues with regional MACs handling the claims.

Pump refill and electronic analysis/programming code valuation: Look at the distribution for these codes and model indirect/direct ratios and practice cost indices and the impact of different specialty mixes. Radensky and Rudolf also are working to confirm current specialty crosswalk for these services with CMS. In addition, they are investigating the status and scope of the AMA’s survey of interventional pain indirect expense and considering the impact on the timing and scope of pursuing the issue with CMS. This will be useful in considering whether new codes may be required.

Join me, please, in making our collective voice heard! Register your concern for patients by sending an email to stoppain@hartleymedical.com today. We will keep you informed on this issue. We’ll also let you know how you can join Hartley Medical in our effort to ensure adequate reimbursement for physicians that preserves this treatment option for patients.

At Hartley Medical, we strive to maintain the optimal environment for compounding sterile drugs. Long before the United States Pharmacopeia (USP) Chapter 797’s guidelines for sterile compounding were introduced, we initiated an effective environmental monitoring program that incorporates advanced technology.

It is important to understand value of Hartley Medical’s equipment associated with exceeding USP 797 regulations for the elimination of bacteria and inanimate microbial or inanimate particles for appropriate sterile compounding. USP 797 requires that pharmacies compound sterile products within a Class 100 environment. Classification 100 is an old standard of the Federal 209-E, stating air classifications of Class 1 through 1,000,000, calibrations and defining air cleanliness. Therefore, a Class 100 Laminar Air Flow Workbench (LAFW / IV Hoods) is defined as providing air quality with no more than a hundred 0.5 micron-size particles to be contained within a cubic foot of air. The ISO 9000 Publication has now revised those past standards, defining the new classification of ISO with a number between 1 and 10. The ISO standards stipulate that Class 100 filtration devices represent an ISO classification of 5. With regard to ISO 5 classification, the concentration of air particles cannot exceed 3,520 per cubic meter. The two standards are differentiated through conversion of particle content to the metric system.

At Hartley Medical, we utilize Class 10 IV hoods that deliver a filtration of no more than 10 particles per cubic foot. The average compounding pharmacy is utilizing Class 100 LAFW/IV Hoods. Our greater filtration capacity provides an optimum environment for sterile compounding and exceeds federal standards.

In addition, our IV hoods are tested for microbial and non-viable air particles. USP 797 states that sterile compounding pharmacies will certify the IV hoods every six months. However, at Hartley Medical we certify our IV hoods every 120 days to closely monitor their function and detect any problems in filtration sooner. For microbial testing we employ a Bioscience SAS 100 Air Sampler. This device will draw 1,000 liters of air across a growth medium plate, detecting the microbial load that could exist in the IV hood area.

At Hartley Medical, we are ahead of both federal and state guidelines affecting sterile compounding. Please review the Polyanalgesic Consensus Conference publication discussing pharmacy compounding and compare its standards with those of Hartley Medical.

Bupivacaine is a local and central nervous system anesthetic drug originally discovered in 1957 along with mepivacaine. German chemical engineers isolated bupivacaine from a compound called cinchocaine. Bupivacaine, which has a unique structural design, produces nerve blocks for up to eight hours and is considered a second-line drug for the treatment of pain by the Polyanalgesic Consensus Conference. This drug is often combined with opioid analgesics and, in some cases, is administered as the sole agent for the relief of neuropathic pain. When combined with other drugs such as hydromorphone, morphine, fentanyl or sufentanil there was no drug induced toxicity or complications observed.

Key Studies Establish Stability
Many long-term studies have been performed regarding intrathecal administration of bupivacaine with clonidine or analgesics for the relief of pain. One particular study, again by Lawrence Trissel[1], showed stability of low and high-dose concentrations of morphine sulfate with bupivacaine when packaged in plastic syringes. The study looked at morphine, 5 mg/ml in combination with bupivacaine hydrochloride, 2.5 mg/ml in sodium chloride 0.9%. The findings indicated that there was no loss of morphine or bupivacaine concentrations in the samples that were stored at 4ºC and 23ºC for 60 days.

Additionally, Trissel studied the stability of morphine sulfate, 50 mg/ml and bupivacaine, 25 mg/ml also stored at 4ºC and 23ºC. This study also concluded that there was no loss of potency for up to 60 days. In another study by K.R.Hildebrand[2] et. al., the objective was to show that the drug was effective for relief of pain when administered through an implantable drug delivery device. In this particular study, commercially available bupivacaine at 7.5 mg/ml was incubated at 37°C for 12 weeks within an implantable infusion device. It was revealed that concentrations remained greater than 96 percent in the implantable drug delivery systems. Stability of bupivacaine is well documented in many other publications.

A December 2004 article in the Journal of Pain and Symptom Management showed bupivacaine hydrochloride, 20 mg/ml, morphine sulfate, 50mg/ml and clonidine, 2mg/ml to be stable within an implantable infusion device for 90 days.

Recommended Dosing
At Hartley Medical, we recommend that the starting dose of bupivacaine be maxed out at approximately 1 to 5 milligrams per day. The upper doses of bupivacaine should not exceed 15 milligrams per day. However, various pain physicians in the western United States have utilized bupivacaine for the treatment of both cancer and non-cancer pain, with doses ranging from 30 to 40 mg/day.

Pivotal Role as Anti-Microbial
A very significant study of bupivacaine was published by Per H. Rosenberg, M.D., and Olli V. Renkonen[3]. The authors examined the anti-microbial activity of bupivacaine and morphine against 10 strains of bacteria. Bupivacaine was studied with various microorganisms, in particular E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus and epidermis. The concentrations of bupivacaine examined were 0.5 mg/ml and 1.25, 2.5, and 5 mg/ml. Bupivacaine in concentrations of 2.5 mg/ml inhibited growth of Staph. epidermis strain and Staph. pyogenes as well as Streptococcus pneumonia. Morphine showed no growth-inhibiting activity against bacteria.

The study’s bottom line is that bupivacaine spurs anti-bacterial activity against common pathogens. More significantly, bupivacaine has specific inhibitory effects on Staphylococcus aureus and Staphylococcus epidermis commonly found on human skin. Bupivacaine has a maximum solubility at 40 mg/ml at room temperature. However, bupivacaine’s solubility increases with temperature; therefore, bupivacaine in concentrations exceeding 40 mg/ml can be stable in an implantable infusion device at 37ºC. However, bupivacaine 40mg/ml stability may be compromised when combined with other drugs within an implantable infusion device.

The drug clonidine hydrochloride was synthesized in 1962 as a derivative of a known alpha sympathomimetic drug, naphazoline, which proved to be an effective treatment for mild to severe hypertension. Clonidine was discovered by scientists at Boehringer and marketed under the brand name of Catapres. It is classified as an alpha 2 adrenergic agonist for the treatment of high blood pressure. The drug acts centrally to inhibit sympathetic tone on systemic blood vessels and thereby reduces hypertension.

More recently, clonidine was discovered to have analgesic properties when administered intraspinally. Currently, it is administered for the treatment of chronic and neuropathic pain. Clonidine has been studied extensively for the treatment of pain. Ackerman[1] published findings on the clinical effectiveness of intraspinal clonidine in 15 patients treated for either neuropathic chronic pain or cancer pain. All patients received single dose injections of clonidine. Patients reported a significant decrease in pain by at least 50 percent utilizing VAS Scale. The Polyanalgesic Consensus Conference 2007 publication recognized clonidine as a second-line drug.

K.S. Filos[2] conducted a double blind study of 20 patients with intrathecal clonidine. The drug was shown to be effective in the relief of secondary pain during a Cesarean section. In this study, patients were receiving 150 micrograms intrathecally versus saline, and their scores demonstrated a significant relief of pain.

Stability
Clonidine displays stability with many narcotic opioid analgesics, as well as anesthetics, and can be administered as a sole agent for the treatment of pain via an implantable infusion pump. It is stable in various concentrations with opioid analgesics. Stability studies of long-term use of intrathecal clonidine have been documented as far back as the early 1990s. One study by Lawrence Trissel[3], et al, showed physical and chemical stability of low and high-concentration morphine in combination with clonidine hydrochloride in plastic syringes. The study established the stability of morphine sulfate, 5 and 50 mg/ml with clonidine, 250-4000 mcg/ml for 60 days. At the conclusion of this study, there was no significant degradation of morphine sulfate or clonidine hydrochloride content when stored in plastic syringes at 4°C and 23°C.

A.M. Classen, et al[4], performed a study analyzing the stability of morphine, bupivacaine and clonidine within the Medtronic infusion device. This study showed the chemical stability of a combination of morphine sulfate, 50 mg/ml, bupivacaine, 20 mg/ml, and clonidine, 2000 mcg/ml. These combination solutions were placed in the reservoir of an implantable infusion pump and stored at 4°C and 37°C for 90 days.

Investigators studied each drug at various points in time, starting with day one and then assessing after 30, 60, and 90 days. High performance liquid chromatograph (HPLC) was used to determine quantitative analysis. At the conclusion of the study, all three drugs remained stable up to 90 days.

Dosing Considerations
Clonidine is an effective drug for the treatment of pain, but therapy should be introduced slowly starting with initial doses of 50 to 100 micrograms per day. Clonidine dosing should be based upon the patient’s condition, pain level, age, weight, and pre-existing conditions. Discontinuing a patient’s treatment with intraspinal clonidine therapy should be done in a cautious manner. A slow titration to remove the clonidine from intraspinal infusion should also be performed. At the conclusion of therapy or after the complete withdrawal of clonidine, consider oral or topical treatment of clonidine for a period of three to seven days to prevent adverse reactions. Clonidine has a solubility of 76.9 mg/ml at room temperature, 20ºC. Clonidine hydrochloride in solution exists in a non-ionic form. This property allows it to penetrate the brain to a much greater degree; it also enables the drug to have a positive effect on tissues and receptors within the brain to relieve systemic vascular tone, thereby giving it anti-hypertensive properties. Side-effects associated with clonidine are hypotension, drowsiness and lethargy.

Hydromorphone is a semi-synthetic opioid discovered in Germany in 1921 and introduced into clinical practice in 1926. Hydromorphone is structurally similar to morphine acting on ? receptors and, to a lesser extent, delta receptors. This drug is often considered a second-line drug for pain management.

Hydromorphone is four to five times more potent than morphine sulfate, with a maximum solubility of one gram in 4 mlf. of water. This high solubility enables the drug to be administered subcutaneously as well as intrathecally. While the compound is not FDA approved for intrathecal administration, the drug’s use as such is well documented. Clinically, hydromorphone is administered with many common intrathecal drugs with no loss of potency noted. Hydromorphone is more lipophilic than morphine-sulfate and, because of less rostral spread, a clinician could expect less narcotic to reach the vomiting center.

A landmark study published in the Journal of Pain and Symptom Management in 2001 established the stability of hydromorphone.[1] Keith Hildebrand, DVM, PhD, and his colleagues documented the drug’s stability when contained in a SynchroMed infusion device maintained at 37 degrees C. The authors found hydromorphone to be stable for four months within the infusion device.

A case report published in Journal of Neurosurgery in 1986[2] by Dennis W. Coombs, MD, et al., presented a case study of a 49- year-old woman with stage 1 uterine carcinoma. Due to the metastasis and subsequent radiation and chemotherapy, her pain required aggressive treatment. This patient was implanted with an infusion device and began to receive intrathecal hydromorphone.

Two months post-implantation, a trial of 0.3mg clonidine was administered IT with almost complete relief of pain. A new drug regimen of hydromorphone and clonidine was very effective and stable. Coombs’ unpublished data substantiate stability of clonidine and hydromorphone at 37° C within an infusion device.

A dosing of hydromorphone, as I stated, is four to five times more potent than morphine; however, at Hartley Medical we suggest a conservative, one to five hydromorphone to morphine conversion. Initial dosages of intrathecal hydromorphone in opiate-naïve patients should start out at 0.1 to 0.2mg per day.
The reimbursement of hydromorphone involves a paradoxical effect. In low concentrations, 1-5mg/ml, most insurance claims are reimbursed less than pharmacy charge. However, for concentrations exceeding 5mg/ml, insurance reimbursements should cover the cost of the drug, depending on pharmacy providers.

At Hartley Medical, we strive to maintain the optimal environment for compounding sterile drugs. Long before the United States Pharmacopeia (USP) Chapter 797’s guidelines for sterile compounding were introduced, Hartley Medical had an effective environmental monitoring program that incorporates advanced technology.

For the last decade, we have monitored microbial air quality with the use of passive plates and augmented this practice with an active air-sampling program. (See July 10, 2007 post.)

An additional component of Hartley Medical’s comprehensive air quality management program is monitoring for very small dust particles, 0.3 to 5.0 microns in dimension, which can transport bacteria. This objective is critical to maintaining air quality, as bacteria attached
to minute air particles may possibly contaminate sterile compounded preparations. Employing a Met One laser particle counter, we assess our air quality daily. On a weekly basis, our extensive evaluation includes sampling the air in seven locations throughout each room in the sterile preparation area. We are trending and analyzing our collected data for future publication.

USP guidelines for pharmacies compounding sterile preparations stipulate that the number of air particles for an ISO 6 compounding room will not exceed 10,000 particles per cubic foot. Hartley Medical’s aseptic preparation environment is certified as a Class 1,000 – exceeding the USP Federal guidelines by a factor of 10. Thus, while other pharmacies may adhere to USP regulations by storing and preparing compounds in a room with 10,000 particles per cubic foot, Hartley Medical takes every precaution to protect the sterility of our compounds by operating within a certification of 1,000 particles per cubic foot.

At Hartley Medical, we are proud to integrate the latest environmental testing technology into our leadership in intrathecal medication preparation.
 

Baclofen is an agonist of gamma-amminobutyric acid (GABA), an inhibitory neurotransmitter, which acts on receptors in the brainstem and dorsal horn of the spinal cord. The drug is used primarily in the treatment of such conditions as spinal cord injury, cerebral palsy, and multiple sclerosis; however, the chemical also possesses analgesic properties. Intraspinal administration of baclofen was first studied in 1984 by Richard Penn, MD. In the 1990s, baclofen gained FDA approval for intrathecal administration and in 1991 was approved for administration through the
implantable infusion pump.

At Hartley Medical, we have extensive experience with this drug and its intraspinal application, having quantitatively analyzed it for more than nine years. Treatment with baclofen must take into consideration that the drug has a very small therapeutic window and presents significant withdrawal issues that must be carefully managed.

The product can be compounded in a vast range of concentrations exceeding 4000mcg/ml. However, some reports have proposed baclofen’s instability in concentrations exceeding 2000/mcg/ml. I believe Hartley Medical has perhaps the greatest experience in studying this drug for intraspinal and pump administration, particularly in relation to the enduring storage within an implantable pump for 60 to 90 days. If you would like to discuss this further, please contact me.

Baclofen in Combination
Baclofen can be safely compounded with many medicinals such as fentanyl, sufentanil, ziconotide, and more commonly, morphine and hydromorphone. Baclofen has a good shelf life and sustained stability within an implantable pump.

A study performed and published in Hospital Pharmacy in 2001 showed baclofen and clonidine to be stable in borosilicate test tubes stored at 37° C for 10 weeks. Although the study was not conducted within an implantable device, the results show chemical integrity in combination and resistance to degradation attributed to body temperature. The stability and compatibility of baclofen and morphine were studied and published in the International Journal of Pharmaceutics.

This study determined that both drugs maintained structure when introduced into an implantable device, stored at body temperature, for 30 days.

For some readers, much of what is stated here is review – while to others, it is enlightening. This article describes the properties of fentanyl citrate and the appropriate dosing for converting patients from morphine to fentanyl for intrathecal treatment of chronic pain.

Patented by Janssen Pharmaceuticals in 1963, fentanyl is a potent narcotic analgesic primarily used for spinal analgesia. The drug possesses a high solubility, with a maximum concentration of 25,000 mcg per milliliter. Fentanyl is extremely lipophilic when administered intraspinally. This property limits its spinal distribution, a fact that must be considered in the treatment of pain at the site of nocioception. A review of the literature indicates fentanyl to be 100 times more potent than morphine sulfate for acute pain and 40 to 50 times more potent in chronic pain.

Conversion from Morphine
Often when a physician contacts Hartley Medical for drug conversion assistance, we discuss pertinent literature and then employ mathematical calculations to derive a beginning intraspinal fentanyl dose. We frequently modify our specific calculation of the dosage based on my experience with patients treated with fentanyl. In my many conversations with physicians having extensive experience in fentanyl, these practitioners favored converting patients from morphine to fentanyl utilizing smaller ratios, such as 1/10 to 1/25 of the daily morphine sulfate dose.

With such a broad conversion range, clinicians unfamiliar with intraspinal administration of fentanyl should seek consultation prior to drug conversion. With regard to dosing, the spectrum is also wide for pain providers. Some physicians have reported dosing as low as 4 mcg per day and others, approximately 5,000 mcg per day.

Maintaining Stability
Clinically, fentanyl citrate has been administered intraspinally in combination with many pharmaceuticals. However, there is little published information regarding the stability of fentanyl in combination with such agents. A 1992 study showed fentanyl 20 mcg/ml to be stable with bupivacaine 1.25 mg/ml in normal saline. In a recent publication, David Shields of Elan Pharmaceuticals found fentanyl to be stable when combined with ziconotide. His study is consistent with Hartley Medical’s post-infusion analysis indicating that fentanyl citrate is stable
when combined with other intraspinal pharmaceuticals.