USOO6835194B2 (12) United States Patent (10) Patent No.: US 6,835,194 B2 Johnson et al. (45) Date of Patent: Dec. 28, 2004

(54) IMPLANTABLE DEVICES AND METHODS (52) U.S. Cl...... 604/890.1; 604/891.1; FOR TREATMENT OF PAN BY DELIVERY 604/93.01; 604/131; 604/132; 604/133; OF FENTANYLAND FENTANYL 424/422; 424/449 CONGENERS (58) Field of Search ...... 604/890.1, 891.1, 604/93.01, 131-133; 424/422,449 (75) Inventors: Randolph Mellus Johnson, Half Moon Bay, CA (US); Felix Theeuwes, Los (56) References Cited Altos Hills, CA (US); Edward M. U.S. PATENT DOCUMENTS Gillis, Cupertino, CA (US); Dana Litmanovitz, Sunnyvale, CA (US); 3. A 3.19. RW al. Barbara Laidlaw, San Jose, CA (US); 3,845,770 A 11/1974 Theeuwes et al. James Brown, Los Gatos, CA (US); 3,916,899 A 11/1975 Theeuwes et al. John Culwell, San Francisco, CA (US); (List continued on next page.) James A. Filice, Los Gatos, CA (US); page. Peter Wickman, San Francisco, CA FOREIGN PATENT DOCUMENTS (US); Su-Il Yum, Los Altos, CA (US); WO WO 97/27840 8/1997 Andrew Poutiatine, Redwood City, CA List tinued t (US); John Dinka, Fairfax, VA (US) (List continued on next page.) OTHER PUBLICATIONS (73) ASSignee: psct Corporation, Cupertino, CA Ahmedzai (1997), “New approaches to pain control in patients with cancer.” Eur: J. Cancer, 33(6):S8-A14. (*) Notice: Subject to any disclaimer, the term of this (List continued on next page.) patent is extended or adjusted under 35 U.S.C. 154(b) by Od Primary Examiner Thurman K. Page a -- (b) by 0 days. ASSistant Examiner-Isis Ghali 21) Appl. No.: 10/188325 (74) Attorney, Agent, or Firm-Carol L. Francis; s ppl. No 1188, Bozicevic, Field & Francis LLP, Tom McCracken 22) Filled: Jun. 27, 2002 (5 7) ABSTRACT (65) Prior Publication Data The invention features devices and methods for treatment of US 2003/0088236 A1 May 8, 2003 pain. The drug delivery device is a drug delivery System Related U.S. Application Data adapted for whole implantation in a Subject and to provide pain relief by delivery of fentanyl or a fentanyl congener (63) Continuation-in-part of application No. PCT/US01/43143, (e.g.,.g., Sufentanil)Su over a protracted period of time (e.g.,s' at filed on Nov. 21, 2001, and a continuation-in-part of appli- least 3 dayS O more than 3 days). The device comprises cation No. PCT/US01/06955, filed on Mar. 2, 2001, and a housing, defining a reservoir that contains a drug continuation-in-part of application No. 09/522,535, filed on formulation, a pump operatively connected to the housing So Mar. 10, 2000, now Pat. No. 6,541,021. as to facilitate movement of drug out of the reservoir and out (60) Sysical EEE S. S.E.E. My 3, of the device, and a thermal expansion element which 17, 2001,, proVISIonal provisional application application No. No. 60/250,328,4Uo, Illed filedon Sep. on defines a flow pathway comprising a thermal expansion Nov. 29, 2000, provisional application No. 60/188,263, filed channel to accommodate thermal expansion of formulation on Mar 10, 2000, and provisional application No. 66/125. in the reservoir. The device can further comprise a valve 589, filed on Mar. 18, 1999. positioned within the flow pathway So as to prevent move (51) Int. CI.7 A61K 9/22, A61M 11/00; ment of drug out of the reservoir prior to use. A61M 3/00; A61F 13/00 27 Claims, 13 Drawing Sheets

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U.S. PATENT DOCUMENTS OTHER PUBLICATIONS 3,923.426 12/1975 Theeuwes Anderson et al., (1998), “Alternate routes of opioid admin 3.987,790 10/1976 Eckenhoff et al. istration in palliative care: pharmacologic and clinical con 3,995,631 12/1976 Higuchi et al. cerns.” J. Pharmaceut. Care Pain Sympt. Control. 6:5-21. 3,998.834 12/1976 Janssen et al. Bansinath, et al., (1989), “Hyperglycemia does not modify 4,016,880 4/1977 Theeuwes et al. the pupillary effects of uand Kopiate agonists in mice' J. 4,036.228 7/1977 Theeuwes Ocular Pharmacology, vol. 5(1): 33–43. 4,111,202 9/1978 Theeuwes 4,111,203 9/1978 Theeuwes Bruera et al., (1987), “Use of the subcutaneous route of the 4,167,574 9/1979 Janssens administration of narcotics in patients with cancer pain' 4.203,440 5/1980 Theeuwes Cancer, vol. 62(2): 407-411. 4.203,442 5/1980 Michaels Cherny et al. (1995). “Opioid pharmacotherapy in the 4,210,139 7/1980 Higuchi management of cancer pain' Cancer, Vol. 76(7): 4,327,725 5/1982 Cortese et al. 1283-1293. 4,360,019 11/1982 Portner et al. Clotz et al. (1991). “Clinical uses offentanyl, Sufentanil, and 4.487,603 12/1984 Harris alfentanil” Clinical Pharmacy, vol. 10. 581-593. 4,576.951 3/1986 Rovati et al. Coda et al. . . (1997). “Comparative efficacy of patient 4,582,835 4/1986 Lewis et al. controlled administration of morphine, hydromorphone, or 4,588,580 5/1986 Gale et al. Sufentanil for the treatment of oral mucositis pain following 4,627,850 12/1986 Deters et al. bone marrow transplantation” Pain, vol. 72: 333-346. 4,681,560 7/1987 Schulte et al. Coyle et al. . . (1994), “Subcutaneous opioid infusions at 4,692,147 9/1987 Duggan home.” Oncology, 8 21-27. 4,725,852 2/1988 Gamblin et al. 4,769,372 9/1988 Kreek Crane (1994). “Intermittent subcutaneous infusion of opio 4,781,924 11/1988 Lee et al. ids in hospice home care: An affective, economical, man 4,865,845 9/1989 Eckenhoff et al. ageable option Am. J. Hospice & Palliative care, vol. 5,057,318 10/1991 Magruder et al. Jan./Feb. 8-12. 5,059,423 10/1991 Magruder et al. Chasmana et al... (1987) “Gastrointestinal transit following 5,112,614 5/1992 Magruder et al. inthrathecal or Subcutaneous narcotic analgesies' Arch. Int. 5,137.727 8/1992 Eckenhoff Pharmacodyn., vol. 286: 152-161. 5,180,716 1/1993 Yaksh et al. Fine (1997), “Fentanyl in the treatment of cancer pain.” Sem. 5,187.177 2/1993 GarZaran Oncol., 24(16) S16–S27. 5,234,692 8/1993 Magruder et al. Finley (1990), “Pain management with spinally adminis 5,234,693 8/1993 Magruder et al. tered opioids.” Am J. Hosp. Pharm , 47(1):S14-S17. 5,346,903 9/1994 Ackerman et al. Funinaga et al. . . (1988). “Reproductive and teratogenic 5,356,635 10/1994 Raman et al. 5,451,408 9/1995 Mezei et al. effects of Sufentanil and alfentanil in Sprague-Dawley rate” 5,472,943 12/1995 Crain et al. Anesth Analg. Vol. 67: 166-169. 5,486,362 1/1996 Kitchell et al. Geller et al . . . (1993). “A randomized double-blind 5.487,739 1/1996 Aebischer et al. comparison of epidural Sufentanil verSuS intravenous Sufen 5,512.578 4/1996 Crain et al. tanil or epidural fentanyl analgesia after major abdominal 5,580,876 12/1996 Crain et al. surgery” Anesth Anallg. vol. 76: 1243-1250. 5,589.480 12/1996 Elkhoury et al. Jeal et al... (1997), “Transdermal fentanyl A review of its 5,633,000 5/1997 Grossman et al. pharmacologic properties and therapeutic efficacy in pain 5,660,854 8/1997 Haynes et al. 5,672,167 9/1997 Athayde et al. control.” Drugs, 53:109-138. 5,728,396 3/1998 Peery et al. Kerr et al. . . (1988), “Continuous narcotic infusion with 5,729,396 3/1998 Dudley et al. patient-controlled analgesia for chronic cancer pain in out 5,747,058 5/1998 Tipton et al. patients.” Ann. Intern. Med., 108:554–557. 5,767,125 6/1998 Crain et al. Kingery (1997), “A critical review of controlled clinical 5,798,114 8/1998 Elsberry et al. trials for peripheral neuropathic pain and complex regional 5,858,388 1/1999 Grossman et al. pain syndromes.” Pain, 73:123-139. 5,861,248 1/1999 Russell et al. Leelanuntakit (1996), “Management of cancer-related pain 5,866,164 2/1999 Kuczynski et al. 5,980,927 11/1999 Kuczynski et al. with transdermal fentnyl' J. Med ASSOC. Thai, vol. 5,985,305 11/1999 Peery et al. 79)6):341–346. RE36,547 2/2000 Crain et al. Manin et al. (1983), “Epidural and intrathecal narcotics.” 6,096,756 8/2000 Crain et al. Can. Anaesth SOc J, 30 662–673. 6,203,813 3/2001 Gooberman Moulin et al... (1992) “Subcutaneous narcotic infusions for 6,245,351 6/2001 Nara et al. cancer pain treatment outcome and guidelines for use” Can. 6,395.292 5/2002 Peery et al. Med. Assoc. J., vol. 146(6), 891-897. 6,436,091 8/2002 Harper et al. Mucha et al... “Parket and Radow test of drug withdrawal aversion opposite effect in rats chronically infused with FOREIGN PATENT DOCUMENTS Sufentanil or amphelamic' Pharmacology Biochem. & WO WO 97/49391 12/1997 Behavior. vol. 35: 219–224. WO WO 98/51246 A 11/1998 Paix et al... (1995), “Subcutaneous fentanyl and Sufentanil WO WO 99/36071 7/1999 infusion Substitution for morphine intolerance in cancer pain WO WO OO/54745 A2 9/2000 management’ Pain, vol. 3: 263-269. US 6,835,194 B2 Page 3

Satterlee (1991). “Ctiteria for use of fentanyl citrate, Sufen Van den Hoogen et al. (1988) “Respiratory effects of tanil citrate, and alfentanil hydrochloride Clinical Phar epidural and Subcutaneous morphine, meperdine (pethi macy. vol. 10: 635-637. Shaw (1993), “Treatment of intractable cancer pain by dine), fentanyl and Sufentanil in the rat Anesth Analg, Vol. electronically controlled parenteral infusion of analgesic 67 1071-1078. drugs.” Cancer, 72:3416–3425. Skaer (1993), “Management of pain in the cancer patient.” Vertafridda et al... (1987), “Intraspinal morphine for cancer Clin. Ther., 15:638-649. pain.” Acta Anaesthesiol Scand., 31(85):47-53. Slattery et al. . . (1985), “Newer methods of delivery of opiates for relief of pain.” Drugs 30.539-551. Wagner et al... (1997) “Pharmacokinetics and pharmaco Sjøgren et al . . . (1994), "Disappearace of morphine-in dynamics of Sedatives and analgesicics in the treatment of duced hyperalgesia after discontinuing or Substituting mor agitated critically ill patients' Clin. Pharmacokinet. Vol. phine with other opioid agonists’ Pain, vol. 59: 313–316. 33(6): 426-453. Taverne et al . . . (1992). “Comparative absorption and distribution pharmacokinetics of intravenous and epidural Willens et al. . . (1993). “Pharmacodynamics, pharmaco Sufentanil for major abdomincal Surgery' Clin. Pharmacoki kinetics, and clinical uses of fentanyl, Sufentanil, and alfen net, vol. 23(3): 231-237. tanil” Heart & Lung, vol. 22(3): 239-251. Van den Hoogen et al... (1987). “Epidural and subcutan cous morphine, meperidine (pethidine), fentanyl and Sufen Zeiler et a ... (1991), “Kontinuierliche peridurale Sufenta tanil in the rat: Analgesia and other in vivo pharmacologic nil-applikation Zur postoperativen analgesic' Anaesthesisi. effects' Anesthesiology, vol. 66: 186-194. vol. 40: 543-548. U.S. Patent Dec. 28, 2004 Sheet 1 of 13 US 6,835,194 B2

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s g a. g S s s O O O O O O O US 6,835,194 B2 1 2 IMPLANTABLE DEVICES AND METHODS dose administered and the length of the administration FOR TREATMENT OF PAN BY DELIVERY period, can generally only be resolved by discontinuing OF FENTANYLAND FENTANYL opioid administration, which in turn results in the onset of CONGENERS severely painful withdrawal symptoms. Other side effects that can be associated with administration of opioids include CROSS-REFERENCE TO RELATED reduced cough refleX, bronchial spasms, nausea, vomiting, APPLICATIONS peripheral vasodilation, orthostatic hypotension, Vagal impact on the heart, contraction of Smooth muscles This application is a continuation-in-part of: (sphincters), reduced peristaltic motility in the gastrointes U.S. application Ser. No. 09/522,535, filed Mar. 10, 2000, tinal tract (e.g., constipation), urinary retention, changes in now U.S. Pat. No. 6,541,021, which application claims the regulation of body temperature and sleep pattern, and release benefit of U.S. provisional application Ser. No. 60/125,589, of histamine, adrenalin, and anti-diuretic hormone. The filed Mar. 18, 1999; negative effects on respiratory function especially impact PCT application Ser. No. PCT/US01/06955, filed Mar. 2, postoperative patients, who are particularly Susceptible to 2001, which application claims the benefit of U.S. provi 15 depression of respiratory function. Even where the concerns sional application Ser. No. 60/188,263, filed Mar. 10, 2000; regarding Side effects might be outweighed by the Serious and need for pain relief as in terminally ill patients, many doctors PCT application serial no. PCT/US01/43143, filed Nov. Still avoid prescribing opioids due to concerns of abuse of 21, 2001, which application claims the benefit of U.S. Surplus medication by others in contact with the patient, or provisional application Ser. No. 60/250,328, filed Nov. 29, even that their frequent prescription of the drug might lead 2000; to criminal investigation. and this application further claims the benefit of U.S. In addition to the disadvantages listed above pertaining to provisional application Ser. No. 60/323,406, filed Sep. 17, opioids in general, morphine itself has also been associated 2001; and the benefit of U.S. provisional application No. with particular side effects, at times So Severe as to make 25 Such therapy intolerable, especially for patients who are on 60/377.541, filed May 3, 2002; long-term pain therapy or who require high doses of medi each of which applications is hereby incorporated by cation to obtain relief. Some of these side effects associated reference in its entirety. with morphine usage, particularly at high doses, include FIELD OF THE INVENTION nausea and vomiting (see for example Paix et al. (1995) Pain 63:263-9) and severe constipation. In addition, Sjorgen et al. The invention relates to devices and methods for the (1994 Pain 59:313–316) have reported the phenomena of management of pain. Particularly, the invention relates to an hyperalgesia (increased response to certain stimulus which implanted drug delivery device used to deliver a potent is not normally painful), allodynia (Sensation of pain felt pain-killing drug over a protracted period of time. even when Stimulus is not normally painful) and myoclonus 35 asSociated with morphine use. It has been hypothesized that BACKGROUND OF THE INVENTION morphine and its metabolites may induce Such abnormal Many medications are used for the treatment of pain, sensitivity (see, e.g., Sjorgen et al. (1994) Pain 59:313–316). ranging from well known, over-the-counter compounds Such Fentanyl and its congeners were originally developed as as aspirin, acetaminophen, ibuprofen and other non-Steroidal anesthesia agents, and are generally used in the United anti-inflammatory compounds to the newly developed 40 States for the limited purposes of intravenous administration chemical entities Such as the cyclooxygenase II inhibitor in balanced general anesthesia, as a primary anesthetic, or, compounds. Opiates in various forms, including opium, in the case of Sufentanil, for epidural administration during heroine and morphine which derive from the opium poppy, labor and delivery. However, these drugs also have powerful have very powerful analgesic properties. Opiates have been analgesic properties and are Several hundred or thousand widely used for anesthesia as well for the treatment of pain, 45 times more potent than morphine depending on the particu especially where the pain is very Severe. In addition to these lar congener. A few studies have in fact Suggested that natural opiates, many Synthetic opioids have since been fentanyl and its congeners be used instead of morphine due Synthesized including methadone, fentanyl and congeners of to their increased potency and decreased side effects relative fentanyl Such as Sufentanil, alfentanil, lofentanil, carfentanil, to morphine (see e.g., Sjorgen et al. (1994) Pain 59:313–316 remifentanil, etc. Of the opioids, morphine is still the drug 50 and Paix et al. (1995) Pain 63:263-9). Fentanyl and its of choice for management of pain at least in part due to its congeners are, however, more difficult to administer than low cost, the ability of the drug to provide relief from pain morphine Since they are not orally absorbed, are extremely of a variety of origins, and the vast experience with this potent (requiring very precise, accurate dosing of Small drug. Despite its therapeutic advantages and vast experience amounts) and have very short half lives in the body thus with the drug, many pain management experts believe that 55 requiring frequent dosing. For these reasons, conventional morphine and other opioids are under-prescribed for patients methods for delivery of opioid analgesics are inadequate to who require long-term pain therapy. meet these delivery requirements. For example, fentanyl has One reason for underprescription is the risk of the Side been administered in Single, Small intravenous doses, but effects associated with long-term administration of opioids this method of administration, besides being impractical for in general, Such as development of opiate tolerance, 60 long-term therapy, results in a short duration of action and dependence, constipation, and/or other undesirable side rapid recovery due to a redistribution into fat Stores and a effects (see, e.g., Moulin et al. 1992 Can Med. ASSOC. J. rapid decline in plasma concentration. The development of 146:891-7). Patients who develop opioid tolerance require transdermal patch delivery technology allowed fentanyl to increased doses to achieve a Satisfactory analgesic effect, be delivered continuously through the skin (e.g., the com and risk the development of further undesirable side effects 65 mercial Duragesic" transdermal patch). Since the transder Such as respiratory depression, which can be life threatening. mal delivery method provided for constant drug delivery, it Physical dependence, which is related to factorS Such as the was a marked improvement relative to bolus injection; US 6,835,194 B2 3 4 however, transdermal delivery also has Several limitations. the device comprising a housing defining a reservoir, the For example, transdermal delivery is disadvantageous in that reservoir containing a formulation comprising a drug the dose of drug that can be delivered is limited by the Selected from the group consisting of fentanyl or a fentanyl available skin Surface area, thus making transdermal deliv congener, wherein the drug is present in an amount Sufficient ery Suitable for low-to-medium opioid dose requirements, for treatment of pain in a Subject for a period of at least about but often inadequate for more high dose requirements. In 3 days, a pump operatively connected to the housing, and a addition, transdermal delivery of drug is disadvantageous in thermal expansion element comprising an inlet, a thermal that there is a delay in obtaining Steady State plasma con centrations upon initiation of therapy, as well as a prolonged expansion channel adapted to contain a volume of formu period of continued effect even after removal of the patch. lation associated with thermal expansion. In use, the inlet, Other problems associated with transdermal delivery thermal expansion channel, and outlet define a flow pathway include skin irritation, loss of adhesion after exposure to from the reservoir and out of the device Such that actuation moisture (e.g., perspiration, bathing) the potential for diver of the pump effects movement of formulation through the Sion of drug for illicit purposes and patient distaste for the flow pathway. unsightliness of highly visible patches. In Specific embodiments, the thermal expansion element While subcutaneous infusion of fentanyl and Sufentanil 15 comprises a flow pathway that is at least partially defined by have been the Subject of experimentation on a limited basis, a plug, which plug can be Seated within the housing. In other the methods disclosed in the prior art are impractical as embodiments the thermal expansion element comprises a long-term pain therapies. Paix et al. (1995 Pain 63:263-9), flow pathway is at least partially defined by a plug Seated for example, discloses the use of Subcutaneous fentanyl and within the device housing, and by the plug and an inner wall Sufentanil as an alternative therapy in a Small number of of the housing. patients who Suffered Significant Side effects associated with In further specific embodiments, the thermal expansion administration of morphine. In Paix et al., the drug was element comprises a valve positioned and adapted for main infused into the Subcutaneous Space in relatively low drug taining a Sealed reservoir until opened. In related concentrations and at relatively large Volume rates (e.g., on embodiments, the thermal expansion element comprises a the order of 3 mL/day to 40 mL/day) via an external syringe 25 plunger, the plunger having at least a portion slidably driver. The treatment method disclosed by Paix et al. has positioned within the flow pathway and having a portion Several major disadvantages that render it impractical for Seated within the valve Such that when in a closed position long-term therapy. First, the provision of drug from an the plunger and valve occlude the flow pathway to prevent external Source adversely affects mobility of the patient and movement of formulation out of the outlet. is therefore inconvenient for ambulatory patients, increases In further specific embodiments, the flow pathway nar the risk of infections at the Subcutaneous delivery site and rows from a wider inlet and thermal expansion channel to a provides an opportunity for drug to be diverted for illicit narrower outlet. uses. Second, the infusion of large Volumes of fluid may In still further embodiments, the device is adapted for result in tissue damage or edema at the Site of infusion. In delivery of drug at a rate of from about 0.01 micrograms per addition, the absorptive capacity of the Subcutaneous space 35 limits the Volume of fluid that can be delivered (See, e.g., hour to 2000 micrograms per hour. Anderson et al., Supra), and this volumetric limitation can in In another embodiment, the drug in the formulation in the turn limit the amount of drug that can be administered (e.g., reservoir is present in a concentration of about 5 mg/mL to in Paix et al., more potent opioids were administered to Some about 400 mg/mL. patients requiring high doses Since the Volume of morphine 40 In an embodiment of particular interest, the drug is required was too large to be effectively absorbed in the Sufentanil. Subcutaneous tissues). In another aspect, the invention features a method of AS is evident from the above, there is a great need for treating pain in a Subject, the method comprising wholly devices and methods for effective and practical management implanting at an implantation site in a Subject a drug of pain, particularly pain of long duration, with better 45 delivery device as described above, and parenterally deliv efficacy and reduced Side effects. The present invention ering the formulation from the drug delivery device to the addresses this problem. Subject So that drug enters the Systemic circulation and is transported thereby to a Site of action in an amount Sufficient SUMMARY OF THE INVENTION to treat pain. The invention features devices and methods for treatment 50 In Specific embodiments, the drug delivery device is of pain. The drug delivery device is a controlled drug implanted at a Subcutaneous site from which drug delivered delivery System adapted for whole implantation in a Subject from the device is released into the Subcutaneous site, and and to provide pain relief by delivery of fentanyl or a then into the Systemic circulation. In further specific fentanyl congener (e.g., Sufentanil) over a protracted period embodiments, the formulation is delivered at a volume rate of time (e.g., at least about 3 days or more than about 3 55 of from about 0.01 ul/day to 2 ml/day. In still other days). The device comprises a housing defining a reservoir embodiments, the drug is delivered at a rate of from about that contains a drug formulation, a pump operatively con 0.01 lug per hour to 2,000 ug per hour. In further nected to the housing So as to facilitate movement of drug embodiments, drug is delivered for a period of from about out of the reservoir and out of the device, and a thermal 4 weeks to 12 months. In another embodiment, the device expansion element which defines a flow pathway comprising 60 comprises an amount of drug Sufficient to provide for a thermal expansion channel to accommodate thermal alleviation of pain in a subject for a period of more than 30 expansion of formulation in the reservoir. The device can days. In an embodiment of particular interest, the drug is further comprise a valve positioned within the flow pathway Sufentanil. So as to prevent movement of drug out of the reservoir prior One advantage of the invention is that the devices and to use. 65 methods described herein provide effective management of Accordingly, in one aspect the invention features a con pain by administration of a relatively Small quantity of trolled drug delivery device, adapted for whole implantation, fentanyl or a fentanyl congener (e.g., Sufentanil), providing US 6,835,194 B2 S 6 adequate pain relief and an improvement in adverse side Still another advantage is that the invention may decrease effects relative to opioids, Such as morphine (e.g., decreased the Severity or incidence of Side effects normally associated gastrointestinal cramping). Given the adverse effects of with use of morphine in pain management. opioid analgesics, this advantage is of considerable benefit Still another advantage is that the invention reduces the to those requiring pain relief, particularly in relatively long potential for diversion of the drug from the intended term (e.g., 1-4 months) pain situations. Furthermore, the recipient, prevents the user from accidental or intentional method may be more cost-effective, and thus may make pain unprescribed alteration of dose, and therefore reduces the management available to a broader population. potential for drug abuse. Another advantage of the invention is that the invention These and other advantages of the invention will be can be used to deliver relatively Small quantities of fentanyl readily apparent to the ordinarily skilled artisan upon read and fentanyl congenerS accurately and precisely and thus ing the present Specification. Safely delivering Such drugs despite the extreme potency of these drugs compared to morphine. Thus, the invention BRIEF DESCRIPTION OF THE DRAWINGS allows for the convenient use of these drugs for treatment of pain ranging in Severity from mild to Severe. 15 FIG. 1 is a graph showing in vitro release of Sufentanil One particular advantage of the invention is that an from exemplary devices comprising an OSmotic pump at a amount of fentanyl or a fentanyl congener Sufficient to rate of 20 tug/hr for a period of about 48 days. provide a relatively long duration of therapy can be stored FIG. 2 is a graph showing cumulative in vitro release of safely and stably within the body and without deleterious Sufentanil from exemplary devices comprising an OSmotic effect given the high potency of the Subject compounds. pump at a rate of 20 tug/hr for a period of about 48 dayS. Another advantage is that the drug delivery devices Stores FIG. 3 is a graph showing in vitro release of Sufentanil the drug formulation safely during use (e.g., without dose from exemplary devices comprising an OSmotic pump at a dumping), and release the drug formulation in a controlled rate of about 5 lug/hr for a period of about 48 days. fashion at a therapeutically effective rate to treat pain. Thus FIG. 4 is a graph showing the average pumping rates the devices and methods of the invention obviate undesir 25 (microliters per day) of the devices of FIGS. 1 and 3, with able bolus delivery upon implantation. an average pumping rate being between about 2 and 2.5 An important advantage of the invention is that the microliters per day. thermal expansion element accommodates thermal expan FIG. 5 illustrates a portion of a thermal expansion element Sion of the formulation in the reservoir, thus minimizing the comprising a valve in a position at which flow is prevented. risk of initial increase of drug release due to thermal This embodiment of the thermal expansion element both expansion of the formulation upon implantation into the compensates for thermal expansion of the drug contained in body. the reservoir, and also allows the drug delivery device to be Another notable advantage of the invention is that the use kept closed and Sealed until just prior to implantation. of an implantable drug delivery device avoids the need for 35 FIG. 6 illustrates the delivery device as in FIG. 5, but with placement of external needles and/or catheters in the Subject, the valve of the thermal expansion element positioned to which cause discomfort and can provide Sites Susceptible to allow flow from the delivery device. infection. In addition, use of an implanted device increases FIG. 7 is a cut-away view of a thermal expansion element patient compliance with a prescribed therapeutic regimen, positioned for use in the housing of a drug delivery device. Substantially decreases or completely avoids the risk of 40 FIG. 8 is a cut-away view of drug delivery device abuse of the drug by the patient or others in contact with the comprising an osmotic pump containing osmotic (salt) patient, and affords greater mobility and easier outpatient tablets, and a Sufentanil formulation. The thermal expansion management. element in this embodiment comprises a valve shown in the Another advantage of the invention is that fentanyl or a Sealed position. fentanyl congener can be delivered into the Systemic circu 45 lation with Such accuracy and precision and at Such low FIG. 9 relates to EXAMPLE5 and shows in vitro release quantities as to permit long-term use of Such compounds to rate data for drug delivery device comprising an OSmotic treat pain. pump System using the embodiment as shown in FIG. 8. FIG. 10 relates to EXAMPLE 5 and shows Sufentanil A further advantage is that a therapeutically effective dose (ug/hour) released in vitro plotted against collection interval. of fentanyl and fentanyl congeners can be delivered at Such 50 relatively low Volume rates, e.g., from about 0.01 ul/day to Thin lines represent data from each of six individual devices. 2 ml/day So as to minimize tissue disturbance or trauma. The thick line indicates the mean value; error bars represent Another advantage of the invention is that Substantially standard deviations (SD). continuous delivery of Small quantities of fentanyl or fen FIG. 11 relates to EXAMPLE 7 and shows plasma con tanyl congener (e.g., Sufentanil) is effective in long-term 55 centrations of Sufentanil before and during induction of (e.g., chronic) administration (e.g., from Several weeks or experimental fever are shown. Each line represents data from about 1 to 12 months or more). from an individual human Subject. The method of the invention is also advantageous in that FIG. 12 is a graph showing plasma Sufentanil concentra Since the Selected drugs (e.g., Sufentanil) are highly lipo tion following implantation. philic relative to other opioids, thus facilitating delivery of 60 FIG. 13 is a graph showing Sufentanil plasma concentra the drug across the blood-brain barrier. For example, the tion (Cp), normalized to a dose 1 microgram/hr following octanol/water partition coefficient of Sufentanil is 1,727, implantation. compared to a coefficient of 1.4 for morphine. Systemic Before the present device and methods for treatment of administration (e.g., by Subcutaneous delivery) of certain pain are described, it is to be understood that this invention lipophilic fentanyl congeners, e.g., Sufentanil, may be as 65 is not limited to the Specific methodology, devices, thera effective as if the drug were delivered directly to the central peutic formulations, and pain Syndromes described as Such nervous System. may, of course, vary. It is also to be understood that the US 6,835,194 B2 7 8 terminology used herein is for the purpose of describing pain So as to make the Subject more comfortable as deter particular embodiments only, and is not intended to limit the mined by Subjective criteria, objective criteria, or both. In scope of the present invention which will be limited only by general, pain is assessed Subjectively by patient report, with the appended claims. the health professional taking into consideration the It must be noted that as used herein and in the appended patient's age, cultural background, environment, and other claims, the singular forms “a”, “and”, and “the' include psychological background factors known to alter a person's plural referents unless the context clearly dictates otherwise. Subjective reaction to pain. Thus, for example, reference to “a drug delivery device' “Delivery site' as used herein is meant to refer to an area includes a plurality of Such devices and reference to “the of the body to which drug is delivered for entry into the method of delivery includes reference to equivalent Steps Systemic circulation, e.g., a Site which allows Systemic and methods known to those skilled in the art, and So forth. access of drug delivered to the Site. Exemplary delivery Sites Unless defined otherwise, all technical and Scientific compatible with Systemic delivery of drug include, but are terms used herein have the same meaning as commonly not necessarily limited to, Subcutaneous, intravenous, intra understood to one of ordinary skill in the art to which this arterial, intra-muscular, intra-adipose tissue, and intra invention belongs. Although any methods, devices and 15 lymphatic Sites. materials similar or equivalent to those described herein can The term “implantation site' is used to refer to a site be used in the practice or testing of the invention, the within the body of a subject at which a drug delivery device preferred methods, devices and materials are now described. is introduced and positioned. All publications mentioned herein are incorporated herein "Drug delivery device' as used herein is meant to any by reference for the purpose of describing and disclosing the device adapted for whole implantation in a Subject, and compositions and methodologies which are described in the Suitable for delivering the formulations for pain manage publications which might be used in connection with the ment according to the invention. In general, "drug delivery presently described invention. The publications discussed device' as used herein refers to an implantable device that herein are provided solely for their disclosure prior to the provides for movement of drug from a reservoir (defined by filing date of the present application. Nothing herein is to be 25 a housing of the device) by action of an operatively con construed as an admission that the invention is not entitled nected pump, e.g., OSmotic pumps, Vapor pressure pumps, to antedate Such a disclosure by Virtue of prior invention. electrolytic pumps, electrochemical pumps, effervescent pumps, piezoelectric pumps, or electromechanical pump Definitions Systems. The term “drug” as used herein is generally meant to refer “Patterned” or “temporal” as used in the context of drug to fentanyl or a fentanyl congener (e.g., Sufentanil, delivery is meant delivery of drug in a pattern, generally a alfentanil, lofentanil, carfentanil, remifentanil, trefentanil, Substantially regular pattern, over a pre-Selected period of and mirfentanil), as well as formulations comprising one or time (e.g., other than a period associated with, for example more of these compounds. Use of "drug or the phrase a bolus injection). “Patterned” or “temporal” drug delivery "fentanyl or fentanyl congener” is not meant to be limiting 35 is meant to encompass delivery of drug at an increasing, to use of, or formulations comprising, only one of these decreasing, Substantially constant, or pulsatile, rate or range Selected opioid compounds. Furthermore, reference to fen of rates (e.g., amount of drug per unit time, or volume of tanyl alone or to a Selected fentanyl congener alone, e.g., drug formulation for a unit time), and further encompasses reference to “Sufentanil,” is understood to be only exemplary 40 delivery that is continuous or Substantially continuous, or of the drugs Suitable for delivery according to the methods chronic. of the invention, and is not meant to be limiting in any way. The term “controlled drug delivery device” is meant to The term “Subject' is meant any Subject, generally a encompass any device wherein the release (e.g., rate, timing mammal (e.g., human, canine, feline, equine, bovine, etc.), of release) of a drug or other desired Substance contained in which management of pain is desired. 45 therein is controlled by or determined by the device itself The term "systemic delivery' is meant to encompass all and not the environment of use. “Controlled delivery” or parenteral routes of delivery which permit drug to enter into “controlled release” are terms used to describe delivery of the Systemic circulation, e.g., intravenous, intraarterial, drug using Such a device. intramuscular, Subcutaneous, intra-adipose tissue, intra “Operatively connected” as used herein means the com lymphatic, etc. 50 ponents are provided in a device So as to function as The term “therapeutically effective amount” is meant an intended. For example, a pump operatively connected to or amount of a therapeutic agent, or a rate of delivery of a in a housing defining a reservoir of a device of the invention therapeutic agent (e.g., amount over time), effective to is meant to indicate that, upon actuation, the pump provides facilitate a desired therapeutic effect, Such as pain relief. The for movement of formulation out of the reservoir and out of precise desired therapeutic effect (e.g., the degree of pain 55 the device. relief, and Source of the pain relieved, etc.) will vary “Sustained drug delivery” refers to release or administra according to the condition to be treated, the drug and/or drug tion of drug from a Source (e.g., a reservoir) over a pro formulation to be administered (e.g., the potency of the tracted period of time. Sustained drug delivery is in effect fentanyl congener, the concentration of drug in the the opposite of bolus drug delivery. formulation, and the like), and a variety of other factors that 60 By "Substantially continuous” as used in, for example, the are appreciated by those of ordinary skill in the art. In context of “substantially continuous delivery' is meant to general, the method of the invention involves the Suppres refer to delivery of drug (e.g., Sufentanil) in a manner that is Sion or mitigation of pain in a Subject Suffering from pain Substantially uninterrupted for a pre-Selected period of drug that may be associated with any of a variety of identifiable delivery (other than a period associated with, for example, a or unidentifiable etiologies. 65 bolus injection). Furthermore, “substantially continuous” The term "pain management or treatment' is used here to drug delivery can also encompass delivery of drug at a generally describe regression, Suppression, or mitigation of Substantially constant, pre-Selected rate or range of rates US 6,835,194 B2 10 (e.g., amount of drug per unit time, or volume of drug also benefit from prophylactic pain management using the formulation for a unit time) that is Substantially uninter devices and methods of the invention, e.g., prior to traumatic rupted for a pre-Selected period of drug delivery. Surgery. Pain amenable to therapy according to the invention The term “reservoir' refers to a chamber or containment may involve prolonged episodes of pain alternating with Space within a delivery device for Storing an agent to be pain-free intervals, or Substantially unremitting pain that delivered from the delivery device. varies in Severity. The terms “flow path' or “flow pathway” refers to the In general, pain can be nociceptive, Somatogenic, pathway taken by an agent as it is dispensed from a reservoir neurogenic, or psychogenic. Somatogenic pain can be mus cular or skeletal (i.e., Osteoarthritis, lumbosacral back pain, of a delivery device to the outside of the delivery device. posttraumatic, myofascial), Visceral (i.e., pancreatitis, ulcer, DETAILED DESCRIPTION OF THE irritable bowel), ischemic (i.e., arteriosclerosis obliterans), INVENTION or related to the progression of cancer (e.g., malignant or non-malignant). Neurogenic pain can be due to posttrau The invention relates to an implanted controlled drug matic and postoperative neuralgia, can be related to neuro delivery device, which in certain embodiments comprises a 15 pathies (i.e., diabetes, toxicity, etc.), and can be related to miniature pump, where the drug delivery device effects nerve entrapment, facial neuralgia, perineal neuralgia, delivery of fentanyl or a fentanyl congener, e.g., Sufentanil. postamputation, thalamic, causalgia, and refleX Sympathetic The housing of the device defines a reservoir in a drug dystrophy. formulation for delivery is contained. The device further Specific examples of conditions, diseases, disorders, and comprises a thermal expansion element, which defines a origins of pain amenable to management according to the flow pathway (or orifice) having an inlet, an outlet, and a present invention include, but are not necessarily limited to, thermal expansion channel between the inlet and outlet. The cancer pain (e.g., metastatic or non-metastatic cancer), thermal expansion channel compensates for initial thermal inflammatory disease pain, neuropathic pain, postoperative expansion of a liquid drug formulation contained in a pain, iatrogenic pain (e.g., pain following invasive proce reservoir of the device after device is implanted in the body 25 dures or high dose radiation therapy, e.g., involving Scar of a Subject. In various exemplary embodiments, the thermal tissue formation resulting in a debilitating compromise of expansion element comprises a plug, or a plug and an inner freedom of motion and Substantial pain), complex regional wall of the device housing. Various portions of the flow pain Syndromes, failed-back pain (e.g., acute or chronic back pathway of the thermal expansion element can be defined by pain), Soft tissue pain, joints and bone pain, central pain, the plug and/or the plug and an inner wall of the housing in injury (e.g., debilitating injuries, e.g., paraplegia, which the plug is Seated. quadriplegia, etc., as well as non-debilitating injury (e.g., to The device can also comprise a valve, which is positioned back, neck, spine, joints, legs, arms, hands, feet, etc.)), in the flow pathway defined by the thermal expansion arthritic pain (e.g., rheumatoid arthritis, osteoarthritis, element So as to prevent leakage of drug from the pump prior arthritic Symptoms of unknown etiology, etc.), hereditary to use or upon implantation. This device can be implanted 35 disease (e.g., Sickle cell anemia), infectious disease and into a patient to provide pain relief over a protracted period resulting Syndromes (e.g., Lyme disease, AIDS, etc.), head of time. The device and flow pathway defined the thermal aches (e.g., migranes), causalgia, hyperesthesia, Sympathetic expansion element are adapted to provide for controlled dystrophy, phantom limb Syndrome, denervation, and the release of fentanyl or fentanyl congener from the reservoir, like. Pain can be associated with any portion(s) of the body, So as to provide an accurate, Sustained delivery of a drug 40 e.g., the musculoskeletal System, Visceral organs, skin, ner over weeks or months. The invention thus finds particular Vous System, etc. use in delivery of fentanyl congeners, Such as Sufentanil, Cancer pain is an example of one broad category of pain which congeners are hundreds of times to thousands of time that can be alleviated according to the methods of the more potent than morphine. invention. One of the underlying causes of cancer pain is the Pain Susceptible to Management with the Devices and 45 Severe local Stretching of tissues by the neoplastic lesion. Methods of the Invention For example, as the cancer cells proliferate in an unrestricted In general, administration of fentanyl or a fentanyl con manner, the tissues in the local region of cancer cell prolif gener according to the invention can be used to facilitate eration are Subjected to mechanical StreSS required to dis management of pain (e.g., palliative care through, e.g., place tissue and accommodate the increased Volume occu Systemic or centrally mediated analgesia) that is associated 50 pied by the tumor mass. When the tumor burden is confined with any of a wide variety of disorders, conditions, or to a Small enclosed compartment, Such as the marrow of a diseases. “Pain' as used herein, unless Specifically noted bone, the resulting pressure can result in Severe pain. otherwise, is meant to encompass pain of any duration and Another cause of cancer pain can result from the aggressive frequency, including, but not limited to, acute pain, chronic therapies used to combat the patient's cancer, e.g., radiation pain, intermittent pain, and the like. Causes of pain may be 55 therapy, chemotherapy, etc. Such cancer therapies can identifiable or unidentifiable. Where identifiable, the origin involve localized or widespread tissue damage, resulting in of pain may be, for example, of malignant, non-malignant, pain. infectious, non-infectious, or autoimmune origin. Of par Pain associated with any type of malignant or non ticular interest is the management of pain associated with malignant cancer is amenable to alleviation according to the disorders, diseases, or conditions that require long-term 60 invention. Specific examples of cancers that can be associ therapy, e.g., chronic and/or persistent diseases or conditions ated with pain (due to the nature of the cancer itself or for which therapy involves treatment over a period of therapy to treat the cancer) include, but are not necessarily Several days (e.g., about at least 3 days to 10 days), to several limited to lung cancer, bladder cancer, melanoma, bone weeks (e.g., about 2 weeks or 4 weeks to 6 weeks), to several cancer, multiple mycloma, brain cancer, non-Hodgkins months or years, up to including the remaining lifetime of 65 lymphoma, breast cancer, oral cancers, cervical cancer, the Subject. Subjects who are not presently Suffering from a OVarian cancer, colon cancer, rectal cancer, pancreatic disease or condition, but who are Susceptible to Such may cancer, dysplastic nevi, endocrine cancer, prostate cancer, US 6,835,194 B2 11 12 head and neck cancers, Sarcoma, Hodgkins disease, skin drug to be delivered. For example, the rank order of potency cancer, kidney cancer, Stomach cancer, leukemia, testicular of fentanyl and Selected fentanyl congenerS relative to cancer, liver cancer, uterine cancer, and aplastic anemia. morphine is as follows: morphine

TABLE 1. Loading Parameters

mg Dose Dose ug delivered delivered Nominal Nominal Device wtfvol% rate rate over 110 over 110 Rate Rate Residence formulation Aughr ag?day days days pul?day Alfhr Volume load 2.5 60 66OO 6.6 1.4 O.O58 155 4.28 5 12O 108OO 10.8 1.4 O.O58 155 8.57 7.5 18O 162OO 16.2 1.4 O.O58 155 12.6 1O 240 216OO 21.6 1.4 O.O58 155 17.1 2O 460 432OO 43.2 1.4 O.O58 155 34.3

These parameters thus dictate the amount of drug to be er's directions. 5% polysorbate 20 was added to the media included in the formulation in order to provide for delivery 50 prior to bringing it to final Volume. This Solution is the at the Selected dose rate for an approximately 110 day period release media (RM). 6 mL of RM was dispensed into a 15 (e.g., about 3 months). mL conical polypropylene tube, with one tube prepared for each system to be tested. The tubes were placed in a 37 C. Example 3 water bath and allowed to reach temperature. 55 A System containing Sufentanil is placed into each tube Formulations Comprising Sufentanil in Benzyl with orifice end down, and completely immersed in the RM. Alcohol At desired time intervals, the System is removed from the tube using a transfer rod. The System is placed (orifice end 397 mg/mL formulation: 3.97g of Sufentanil base were down) into a new tube of RM which has been equilibrated weighed out and added to a portion of benzyl alcohol. The 60 in the water bath. An example of time intervals is 0.5 hours, drug was dissolved in the benzyl alcohol by Stirring with a 1, 2, 3, 4, 5, 6, 7, 14, 28, 35 days, continuing weekly until magnetic Stirrer. When the resultant preparation was clear, delivery is complete. additional benzyl alcohol was added to obtain 10 mL of In order to determine the amount of Sufentanil released, 4 formulation. The resultant formulation concentration was mL of acetonitrile was added to each Sample test tube and 397 mg/mL. 65 mixed thoroughly. The Sample is then assayed to determine 310 mg/mL formulation: 3.10 g of Sufentanil base were the amount of Sufentanil released during the time interval. weighed out and added to a portion of benzyl alcohol. The Sufentanil in the samples was quantitated by HPLC or other US 6,835,194 B2 27 28 methodology capable of quantitating Sufentanil in the pres ratio. 3: Implant a drug delivery device into a patient which ence of formulation and RM. The amount released per unit provides the appropriate dosage. 4: Continue Duragesic for time was calculated for each interval, and a release rate one patch cycle until drug delivery is initiated from the drug profile prepared by plotting the amount released per unit delivery device. time on the y-axis against the mean time interval on the The methods employed were as follows: X-axis. A conversion protocol was devised to allow easy conver The results for the 20 tug/hr system are provided in FIG. Sion of patients from their previous opioid medication to 1, with the cumulative release provided in FIG. 2. The Sufentanil implants. The Strategy generally followed the results for the 5 lug/hr system are provided in FIG. 3. The Steps: 1) Quantify present opioids as "oral morphine equiva average pumping rate for each group (the 20 tug/hr group of lents. 2) Apply appropriate Duragesic.E patch. 3) Titrate devices and the 5 ug/hr group of devices) is provided in FIG. Duragesic(R) dose till stable. 4) Convert fentanyl dose to 4. The results demonstrate that controlled, continuous, and Sufentanil dose. 5) Implant a device containing Sufentanil. precise low volume release of the potent opioid Sufentanil is The following conversion table was produced: achieved with an implanted device comprising a pump. In vitro release by the device is correlated to in vivo release 15 because the Volume dispensed from the device is a pure function of the pump and is independent of the environment Duragesic (E) (ug/hr) Equivalent Invention delivery rate TM (ug/hr) Surrounding the pump. Thus, these same devices are 25 3.3 expected to perform the same in Vivo as in vitro. 50 6.7 75 1O.O Example 5 1OO 13.3 In Vitro Release of Sufentanil from a Device Comprising an Osmotic Pump Eighteen patients with chronic pain of various etiologies provided informed consent to participate in the Study. All In this example a device having an osmotic pump as 25 patients were receiving Duragesic, 75 lug/hr or 150 ug/hr, as shown in FIG. 8, having a thermal expansion element and their primary opioid (70% of daily opioid intake) and had valve assembly as in FIGS. 5 and 6. Stable opioid intake (defined, in part, as no change in The housing into which the plug is to be inserted is Duragesic dose in the previous month). Patients underwent approximately 3.150 mm in diameter, and approximately Screening for 1-3 weeks to quantify and establish Stability of 43.18 mm in length. The components were preSS fit together. opioid intake and pain VAS (Visual Analysis Scale) Scores The reservoir of the drug delivery device was filled with (0-10 cm). Based on the relative potency of fentanyl and approximately 155 ul of Sufentanil formulation, formulated Sufentanil being 1:7.5, patients received implants of the with benzyl alcohol to a concentration of about 179.58 invention delivering 10 or 20 tug/hr Sufentanil, respectively. mg/ml. The device was tested by placing the device with the The implant was placed Subcutaneously, just above the plug in place in a 37 C. water bath filled with PBS to 35 elbow, on an outpatient basis using local anesthesia and a Simulate implantation in the body, and measuring the rate of Specially-designed implanter. drug delivery from the device. During the three-day Startup period of the OSmotic System, The results (showing delivery rate (microliters per day) analgesia was provided by continuing the patient's Durag vs. time (days)) are shown in FIG. 9. As can be seen, the 40 esic therapy. After drug delivery approaches Steady State, device dispensed about 1.5 microliters per hour, with Duragesic was discontinued and the patient used short approximately Zero order kinetics, for over 100 dayS. acting opioids, typically oxycodone, to treat breakthrough pain. Opioid intake and VAS score were recorded daily Example 6 during the Six-week implant period. The primary efficacy 45 endpoint was evaluated at day 28 of the implant period. Transition from Transdermal Fentanyl Patch to Outcome was based on a change in VAS Score and SucceSS Delivery of Sufentanil Using Implant ful replacement of previous opioid use. VAS Score was In another example the drug delivery device comprises an categorized as improved (>20% decrease), worse (>20% oSmotic pump and is fitted with a plug defining a flow increase), or unchanged. pathway as shown in FIG. 7. This drug delivery device of 50 The Sufentanil dose was considered correct for that patient this example was employed in a Study in which users of the if: a) the patient showed no signs of opioid overdose during Duragesico(E) patch (fentanyl transdermal patch) were con treatment, particularly during the period during which drug verted to the implanted system of the invention which delivery approached steady State, and, b) if treatment was delivers Sufentanil for six weeks. asSociated with Substantial replacement of previous opioid The Sufentanil delivery rates for this study were 10 55 therapy. Replacement of previous opioid therapy was quan micrograms per hour (at a concentration of 104.4 milligrams tified from the patients total daily breakthrough opioid per ml) and 20 micrograms per hour (at a concentration of medication during treatment and their total daily opioid dose 208.7 milligrams per ml). during Screening, all opioids were quantified as "oral mor The Strategy employed to Select and implant a device phine equivalents” (OME) based on conversion values from comprising a pump that delivers an appropriate dose was as 60 the Opioid Conversion Calculator (Cynergy Group, follows: 1: If a patient is not already using DurageSic Poulsbo, Wash.). At the end of the implant period (no more (transdermal fentanyl, Janssen) as their primary opioid, than 6 weeks of treatment), the implanted drug delivery transition the patient from present opioids to DurageSic device of the invention was explanted under local (according to usual clinical practice, over a six-to-nine day anesthesia, previous opioid therapy was resumed, and period). 2: Once the Duragesic dose is stable and comprises 65 patient global preference was assessed. 70% of daily opioid consumption, convert the patient's Results were as follows: Both the implantation and fentanyl dose to a Sufentanil dose based on a 1:7.5 potency explantation procedure was well tolerated by the patient. No US 6,835,194 B2 29 30 patient demonstrated Signs of overdose during the implant the body or where the delivery rated cannot be readily period. Median opioid replacement was 72%; opioid adjusted (e.g., where the implant is a fixed delivery rate replacement exceeded 50% in 78% of patients. Pain VAS device ). Scores improved or were unchanged in 78% of patients. This example was designed to consider this issue in the Sixty-one percent of patients preferred the implanted device 5 context of the present invention. The Study was conducted to or had no preference. The results are Summarized in the determine the half-life at which the fentanyl congener Sufen following tables. tanil is absorbed from the Subcutaneous space, bioavailabil ity of Sufentanil, and the impact of induced fever on the plasma concentration (Cp) of Sufentanil. It is known that a fever would increase the temperature of the housing of the Opioid Replacement (At Day 28). implanted drug delivery device therefore causing thermal expansion of the formulation, and thereby releasing a Small Number of patients Opioid Replacement bolus of Sufentanil. An experiment was conducted to assess 14 >50% the impact on plasma concentration of Sufentanil released 2 20-50% 15 from an exemplary drug delivery device of the invention in 2 <20% normal human Subjects in the event of a temperature rise *Opioid replacement is defined as 100% - (Duragesic opioid intake during asSociated with a typical fever in humans. If the extra bolus treatment)/(Total opioid intake during screening) of drug released from the drug delivery device of the invention as a result of thermal expansion of the formulation was found to be absorbed rapidly into the Systemic circu lation as indicated by the blood plasma concentration of Pain VAS Score At Day 28 Of Therapy. drug (i.e., the absorption half-life is short), then the methods and devices taught by this invention would have more Pain WAS Score Number of patients limited use in patients who are not monitored by health care Improved 6 25 givers due to Safety concerns. If, however, the drug formu No change 8 lation released as a result of thermal expansion is more Worse 4 Slowly absorbed (i.e., the absorption half-life is long), then *Improved: 20% decrease in pain VAS score a typical fever experienced by a patient using the device of it Worse: 20% increase in pain VAS score this invention would not pose a Safety concern to the patient and would therefore make the device and methods of this invention a more practical and convenient way to treat pain. The drug delivery device used in this example included an oSmotic pump and a thermal expansion element comprising Patient Global Preference After Completion Of Therapy. a plug as shown in FIG. 7 containing a formulation of Patient preference Number of patients 35 Sufentanil at a concentration of about 109 mg/ml and “Very much prefer implant designed to deliver a dosage of 5 micrograms of Sufentanil "Prefer implant” per hour. Based on the thermal expansion coefficient of the “No preference” drug formulation, it is expected that a “typical” fever of 2.5 “Prefer previous therapy C. Should release approximately six hours of formulation. “Much prefer previous therapy 40 Methods were as follows: 1) Consent was obtained from twelve healthy opioid-naive volunteers (six males) aged In conclusion, the absence of Signs of opioid overdose and 19-38 years. Subjects received the opioid antagonist drug the large replacement of previous opioid therapy by the naltrexone, 50 mg orally twice daily, to prevent opioid implant of the invention indicate that the potency ratio used related effects. 2) Drug Administration: On day 0, Subjects in the dose Selection/transition Strategy is appropriate. The 45 received a Solution of Sufentanil citrate, 10 ug/hour, intra patient preference rating shows that more patients prefer the venously (IV) for six hours to establish a reference to implant than prefer the previous therapy. establish the bioavailability of Sufentanil. On day 2, the drug delivery device described above was implanted in the medial Example 7 aspect of the upper arm under local anesthesia. On day 11, 50 the drug delivery device was explanted. 3) Fever induction: Pharmacokinetic Characteristics of the Implant On day 9, half of the subjects received aldesleukin System (interleukin-2, Chiron), 150,000–250,000 IU, to induce a A major concern in the use of implanted device to deliver experimental fever of about 2.5 C. 4) Blood sampling: potent drugs. Such as fentanyl and fentanyl congeners Approximately 50 venous blood Samples were taken from focuses on changes in the environment of use-that is, in the 55 each Subject, Starting before the IV infusion and ending on body of the subject-that could affect delivery rate and the day 14.5) ASSay: Sufentanil concentrations in plasma (Cp) amount of drug delivered. Where a drug as potent as fentanyl were measured using a specific MS-LC-LC assay Sensitive or a fentanyl congener is administered, even a very minute to 2 pg/ml (CV-9% at that concentration). change in the delivery profile can have Severe effects on the Pharmacokinetic modeling: A population analysis was Subject, including over-dose with attendant Side effects Such 60 performed using nonlinear mixed effects modeling as respiratory depression and even death. Of particular (NONMEM). Initially, systemic pharmacokinetics (2-vs. concern are unpredictable and unexpected fluctuations in 3-compartment models) were estimated based on the IV body temperature, Such as those associated with fever often dose of Sufentanil. Absorption from the drug delivery device experienced with a flu or other illness. These concerns are was then modeled as a first-order process (based on all data, even more Serious where the drug is to be delivered through 65 except those during induced fever). Release rate was mod use of an implant that contains a highly concentrated for eled as a linear spline with four knots. The first and fourth mulation of the drug which cannot be readily removed from knots were positioned at time of implant and explant, US 6,835,194 B2 31 32 respectively. The height of all knots and the time of the two a given individual was relatively constant throughout the intermediate knots were estimated. Cumulative release over Study, and that the average plasma level varies between the implant period was calculated from the post hoc about 0.01 and 0.04 ng/ml for this normalized set. (individual) estimates of the release rate profiles and com This Study Supports that the rate of release of Sufentanil is pared by unpaired t-test to the cumulative in vitro release of Steady and within a desired therapeutic range when the drug implant Systems from the same manufacturing lot. delivery device of the invention is implanted in vivo over a Results show that absorption half-life of Sufentanil was period of about 45 days. 16.2 hours, and it appears that fever was not associated with While the present invention has been described with an undesirable Systemic increase of Sufentantil as indicated reference to the specific embodiments thereof, it should be by blood plasma concentrations. Results are shown understood by those skilled in the art that various changes graphically, in FIG. 11. may be made and equivalents may be Substituted without The absorption half-life of Sufentanil is far longer than departing from the true Spirit and Scope of the invention. In that typically associated with intramuscular administration addition, many modifications may be made to adapt a of large Volumes of dilute Solutions of opioids; this may particular situation, material, composition of matter, result from the Small volume administered or the viscosity of 15 process, process Step or Steps, to the objective, Spirit and the highly concentrated benzyl alcohol solution. This Scope of the present invention. All Such modifications are lengthy half-life is desirable-it dampens changes in Cp if intended to be within the Scope of the claims appended physiologic conditions Such as fever alter release from the hereto. drug delivery device. This may partly explain why fever What is claimed is: does not increase Sufentanil Cp Systematically, a Second 1. A controlled drug delivery device, adapted for whole factor is that fever causes physiologic changes Such as implantation in a Subject, the device comprising: increases in cardiac output that may counteract the increased a housing defining a reservoir, the reservoir containing a delivery rate. The foregoing example show the unexpected formulation comprising a drug Selected from the group result that the methods and devices of the present invention consisting of fentanyl or a fentanyl congener, wherein can be used as a Safe and convenient way to treat pain even 25 the drug is present in an amount Sufficient for treatment when there is unexpected fluctuations in the overall body of pain in a Subject for a period of at least about 3 days, temperature of a patient Such as due to fever. a pump operatively connected to the housing, and a thermal expansion element comprising an inlet, a ther Example 8 mal expansion channel adapted to contain a Volume of Delivery of Sufentanil from Implant-Plasma formulation associated with thermal expansion, and an Levels Over a Delivery Period of Approximately outlet, 45 Days wherein in use, the inlet, thermal expansion channel, and outlet define a flow pathway from the reservoir and out A study was conducted to determine in Vivo (human) 35 of the device Such that actuation of the pump effects Sufentanil plasma concentrations produced by an implanted movement of formulation through the flow pathway. drug delivery device of the invention over a period of about 2. The device of claim 1, wherein the flow pathway of the 45 days. The Study employed devices having an OSmotic thermal expansion element is at least partially defined by a pump with a thermal expansion element comprising a plug plug Seated within the housing. as shown in FIG. 7 containing a formulation of Sufentanil, 40 3. The device of claim 1, wherein the flow pathway of the which devices were designed to deliver Sufentanil at doses thermal expansion element is at least partially defined by a of 5, 10 or 20 micrograms per hour. A number of informed plug Seated within the housing, and an inner wall of the consenting patients were Selected for the Study. Each patient housing. was implanted with one or two of the drug delivery devices 4. The device of claim 1, wherein the thermal expansion as described above in order to administer the appropriate 45 element comprises a valve positioned and adapted for main dosage of drug to the patient. Thus, the patients in the Study taining a Sealed reservoir until opened. received a variety of doses of Sufentanil via implanted drug 5. The device of claim 4, wherein the thermal expansion delivery devices ranging from 5-40 micrograms per hour. element comprises a plunger, wherein at least a portion of The plasma levels of Sufentanil of all patients in the study the plunger is Slidably positioned within the flow pathway were measured over a period of about 45 to 50 days. 50 and seated within the valve Such that when in a closed FIG. 12 shows the plasma concentration in ng/ml in a position the plunger and valve occlude the flow pathway to number of the human patients. The y-axis of this graph is prevent movement of formulation out of the outlet. shown as a log Scale. Each line represents an individual 6. The device of claim 1, wherein the flow pathway Subject. The graph shows that the plasma concentration of narrows from a wider inlet and thermal expansion channel to Sufentanil as delivered from the drug delivery devices was at 55 a narrower outlet. a steady rate (near Zero order kinetics) throughout the study, 7. The device of claim 1, wherein the device is adapted for and that the average plasma level varies between about 0.05 delivery of drug at a rate of from about 0.01 micrograms per and 1.00 ng/ml. The variability of the plasma concentration hour to 2000 micrograms per hour. of Sufentanil between individual patients resulted mostly 8. The device of claim 1, wherein said drug is present in from the fact that the patients in the study received differing 60 a concentration of about 5 mg/mL to about 400 mg/mL. dosages of Sufentanil from each other depending on each 9. The device of claim 1, wherein the drug is sufentanil. individual's identified dosage requirement. 10. A method of treating pain in a Subject, the method FIG. 13 shows the plasma concentration in ng/ml in a comprising the Steps of: number of human Subjects. The data has been normalized to wholly implanting at an implantation site in a Subject the a dose of 1 microgram/hr. The y-axis of this graph is shown 65 drug delivery device of claim 1; and as a linear Scale. Each line represents an individual Subject. parenterally delivering the formulation from the drug The graph shows that plasma concentration of Sufentanil in delivery device to the Subject So that drug enters the US 6,835,194 B2 33 34 Systemic circulation and is transported thereby to a site of the device Such that actuation of the pump effects of action in an amount Sufficient to treat pain. movement of formulation through the flow pathway. 11. The method of claim 10, wherein the thermal expan 19. The device of claim 18, wherein the flow pathway of Sion element of the device comprises a valve and a plunger, the thermal expansion element is at least partially defined by at least a portion of the plunger being slidably positioned a plug Seated within the housing. within the flow pathway and seated within the valve such that when in a closed position the plunger and valve occlude 20. The device of claim 18, wherein the flow pathway of the flow pathway to prevent movement of formulation past the thermal expansion element is at least partially defined by the thermal expansion channel in a direction toward the a plug Seated within the housing, and an inner wall of the outlet, and wherein the method further comprises the Step of housing. actuating the plunger So as to open the valve prior to Said 21. The device of claim 18, wherein the thermal expan implanting. Sion element comprises a valve. 12. The method of claim 10, wherein the drug delivery 22. The device of claim 18, wherein the thermal expan device is implanted at a Subcutaneous site. Sion element comprises a plunger, wherein at least a portion 13. The method of claim 10, wherein the formulation is 15 of the plunger is slidably positioned within the flow pathway delivered at a volume rate of from about 0.01 ul/day to 2 and seated within the valve Such that when in a closed ml/day. position the plunger and valve occlude the flow pathway to 14. The method of claim 10, wherein drug is delivered at a rate of from about 0.01 lug per hour to 2,000 ug per hour. prevent movement of formulation through the outlet. 15. The method of claim 10, wherein the drug is Sufen 23. The device of claim 18, wherein said drug is present tanil. in a concentration of about 50 mg/mL to about 400 mg/mL. 16. The method of claim 10, wherein said delivering is for 24. A method of treating pain in a Subject, the method a period of from about 4 weeks to 12 months. comprising the Steps of: 17. The method of claim 10, wherein the device comprises wholly implanting at an implantation site in a Subject the an amount of drug Sufficient to provide for alleviation of 25 drug delivery device of claim 18; and pain in the Subject for a period of more than 30 dayS. parenterally delivering the formulation from the drug 18. A controlled drug delivery device, adapted for whole delivery device to the Subject So that drug enters the implantation in a Subject, the device comprising: Systemic circulation and is transported thereby to a site a housing defining a reservoir, the reservoir containing a of action in an amount Sufficient to treat pain. formulation comprising Sufentanil in an amount Suffi 25. The method of claim 23, wherein the drug delivery cient for treatment of pain in a Subject for a period of device is implanted at a Subcutaneous site. at least about 3 days; 26. The method of claim 23, wherein the formulation is a pump operatively connected to the housing, and delivered at a volume rate of from about 0.01 ul/day to 2 a thermal expansion element comprising an inlet, a ther 35 ml/day. mal expansion channel adapted to contain a Volume of 27. The method of claim 23, wherein the device comprises formulation associated with thermal expansion, and a an amount of drug Sufficient to provide for alleviation of delivery outlet; pain in the Subject for a period of more than 30 dayS. wherein in use, the inlet, thermal expansion channel, and outlet define a flow pathway from the reservoir and out k k k k k