Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners

Abstract

The invention features devices and methods for treatment of pain. The drug delivery device is a drug delivery system adapted for whole implantation in a subject and to provide pain relief by delivery of fentanyl or a fentanyl congener (e.g., sufentanil) over a protracted period of time (e.g., at least 3 days or more than 3 days). The device comprises a housing defining a reservoir that contains a drug formulation, a pump operatively connected to the housing so as to facilitate movement of drug out of the reservoir and out of the device, and a thermal expansion element which defines a flow pathway comprising a thermal expansion channel to accommodate thermal expansion of formulation in the reservoir. The device can further comprise a valve positioned within the flow pathway so as to prevent movement of drug out of the reservoir prior to use.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of: [0002] U.S. application Ser. No. 09 / 522,535, filed Mar. 10, 2000, which application claims the benefit of U.S. provisional application Ser. No. 60 / 125,589, filed Mar. 18, 1999; [0003] PCT application serial no. PCT / US01 / 06955, filed Mar. 2, 2002, which application claims the benefit of U.S. provisional application Ser. No. 60 / 188,263, filed Mar. 20, 2000; and [0004] PCT application serial no. PCT / US01 / 43143, filed Nov. 21, 2001, which application claims the benefit of U.S. provisional application Ser. No. 60 / 250,328, filed Nov. 29, 2000; [0005] and this application further claims the benefit of U.S. provisional application Ser. No. 60 / 323,406, filed Sep. 17, 2001; and the benefit of U.S. provisional application 60 / 377,541, filed May 3, 2002; [0006] each of which applications is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0007] The invention relates to devices an...

AI Technical Summary

Benefits of technology

[0025] One advantage of the invention is that the devices and methods described herein provide effective management of pain by administration of a relatively small quantity of fentanyl or a fentanyl congener (e.g., sufentanil), providing adequate pain relief and an improvement in adverse side effects relative to opioids, such as morphine (e.g., decreased gastrointestinal cramping). Given the adverse effects of opioid analgesics, this advantage is of considerable benefit to those requiring pain relief, particularly in relatively long term (e.g., 1-4 months) pain situations. Furthermore, the method may be more cost-effective, and thus may make pain management available to a broader population.

[0026] Another advantage of the invention is that the invention can be used to deliver relatively small quantities of fentanyl and fentanyl congeners accurately and precisely and thus safely delivering such drugs despite the extreme potency of these drugs compared to morphine. Thus, the invention allows for the convenient use of these drugs for treatment of pain ranging in severity from mild to severe.

[0027] One particular advantage of the invention is that an amount of fentanyl or a fentanyl congener sufficient to provide a relatively long duration of therapy can be stored safely and stably within the body and without deleterious effect given the high potency of the subject compounds.

[0028] Another advantage is that the drug delivery devices stores the drug formulation safely during use (e.g., without dose dumping), and release the drug formulation in a controlled fashion at a therapeutically effective rate to treat pain. Thus the devices and methods of the invention obviate undesirable bolus delivery upon implantation.

[0029] An important advantage of the invention is that the thermal expansion element accommodates thermal expansion of the formulation in the reservoir, thus minimizing the risk of initial increase of drug release due to thermal expansion of the formulation upon implantation into the body.

[0030] Another notable advantage of the invention is that the use of an implantable drug delivery device avoids the need for placement of external needles and / or catheters in the subject, which cause discomfort-and can provide sites susceptible to infection. In addition, use of an implanted device increases patient compliance with a prescribed therapeutic regimen, substantially decreases or completely avoids the risk of abuse of the drug by the patient or others in contact with the patient, and affords greater mobility and easier outpatient management.

Problems solved by technology

Despite its therapeutic advantages and vast experience with the drug, many pain management experts believe that morphine and other opioids are under-prescribed for patients who require long-term pain therapy.

One reason for underprescription is the risk of the side effects associated with long-term administration of opioids in general, such as development of opiate tolerance, dependence, constipation, and / or other undesirable side effects (see, e.g., Moulin et al.

Patients who develop opioid tolerance require increased doses to achieve a satisfactory analgesic effect, and risk the development of further undesirable side effects such as respiratory depression, which can be life threatening.

Physical dependence, which is related to factors such as the dose administered and the length of the administration period, can generally only be resolved by discontinuing opioid administration, which in turn results in the onset of severely painful withdrawal symptoms.

The negative effects on respiratory function especially impact postoperative patients, who are particularly susceptible to depression of respiratory function.

Even where the concerns regarding side effects might be outweighed by the serious need for pain relief as in terminally ill patients, many doctors still avoid prescribing opioids due to concerns of abuse of surplus medication by others in contact with the patient, or even that their frequent prescription of the drug might lead to criminal investigation.

In addition to the disadvantages listed above pertaining to opioids in general, morphine itself has also been associated with particular side effects, at times so severe as to make such therapy intolerable, especially for patients who are on long-term pain therapy or who require high doses of medication to obtain relief.

Fentanyl and its congeners are, however, more difficult to administer than morphine since they are not orally absorbed, are extremely potent (requiring very precise, accurate dosing of small amounts) and have very short half lives in the body thus requiring frequent dosing.

For these reasons, conventional methods for delivery of opioid analgesics are inadequate to meet these delivery requirements.

For example, fentanyl has been administered in single, small intravenous doses, but this method of administration, besides being impractical for long-term therapy, results in a short duration of-action and rapid recovery due to a redistribution into fat stores and a rapid decline in plasma concentration.

Since the transdermal delivery method provided for constant drug delivery, it was a marked improvement relative to bolus injection; however, transdermal delivery also has several limitations.

For example, transdermal delivery is disadvantageous in that the dose of drug that can be delivered is limited by the available skin surface area, thus making transdermal delivery suitable for low-to-medium opioid dose requirements, but often inadequate for more high dose requirements.

In addition, transdermal delivery of drug is disadvantageous in that there is a delay in obtaining steady state plasma concentrations upon initiation of therapy, as well as a prolonged period of continued effect even after removal of the patch.

Other problems associated with transdermal delivery include skin irritation, loss of adhesion after exposure to moisture (e.g., perspiration, bathing) the potential for diversion of drug for illicit purposes and patient distaste for the unsightliness of highly visible patches.

While subcutaneous infusion of fentanyl and sufentanil have been the subject of experimentation on a limited basis, the methods disclosed in the prior art are impractical as long-term pain therapies.

The treatment method disclosed by Paix et al. has several major disadvantages that render it impractical for long-term therapy.

First, the provision of drug from an external source adversely affects mobility of the patient and is therefore inconvenient for ambulatory patients, increases the risk of infections at the subcutaneous delivery site and provides an opportunity for drug to be diverted for illicit uses.

Second, the infusion of large volumes of fluid may result in tissue damage or edema at the site of infusion.

In addition, the absorptive capacity of the subcutaneous space limits the volume of fluid that can be delivered (see, e.g., Anderson et al., supra), and this volumetric limitation can in turn limit the amount of drug that can be administered (e.g., in Paix et al., more potent opioids were administered to some patients requiring high doses since the volume of morphine required was too large to be effectively absorbed in the subcutaneous tissues).

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