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  Coping With The US Opioid Shortage
   
  Dr. Bob Stein
  Updated: December 2018
   
 

US veterinary professionals have had to deal with a mu agonist opioid shortage since late 2017. The outlook for the return of an adequate supply of injectable opioid product has turned decidedly bleak.

Pfizer (who owns Hospira), a major manufacturer of injectable products including opioids and the opioid antagonist naloxone, has announced that they will no longer supply veterinary distributors with opioid product in order to better address the critical opioid shortage within the human healthcare system. This is expected to affect all major veterinary distributors including Amatheon, Schein, MWI, etc. West-Ward and Akorn Pharmaceuticals are not affected at this time.

To help alleviate supply related backlogs the DEA recently increased production quotas for Fresenius Kabi and West-Ward Pharmaceuticals. Unfortunately, it generally takes several months before an increase in production makes an impact at the distributor supply level.

 
   
  Short version
   
 

We will be lucky if we see significant relief with respect to hydromorphone, morphine, and fentanyl supplies before January of 2019. Most of the product that we will see is going to be preservative free and far more expensive per dose which will incur substantially greater logistical challenges with respect to unused product adding additional overall expense.

  • Complete the DEA CSOS application process as soon as possible: https://www.deaecom.gov/
  • Create accounts with as many schedule II drug suppliers as possible:
  • Monitor each supplier’s drug inventory daily and place online CSOS DEA 222 orders immediately.
  • Leverage buprenorphine as much as possible: standard buprenorphine, Simbadol®, and SR buprenorphine.
    • Utilize Simbadol® for all buprenorphine needs. See below for more detail.
  • Consider meperidine as your preanesthetic mu agonist opioid when you cannot obtain morphine or hydromorphone.
  • Include dexmedetomidine whenever appropriate to add substantial stress relief and potentially enhance analgesia.
  • Include an NMDA antagonist in all surgical cases.
  • Use simple local/regional techniques on every case possible:
    • OHEs: intraperitoneal and incisional
    • Neuters: intratesticular and incisional
    • Dental surgery: nerve blocks
    • Orthopedic: periarticular infiltration, nerve blocks, and epidural
    • GI surgery: epidural and incisional
    • Thoracic surgery: epidural, intercostal, intrapleural
    • Foreleg surgery: periarticular infiltration, epidural, nerve blocks
    • Ophthalmic: retrobulbar blocks
    • Amputations: nerve blocks, epidural, soaker catheters
  • Use analgesic lidocaine and ketamine CRIs on every case possible.
  • Adopt the newer, safer EP4 piprant class NSAID Galliprant® to expand the number of patients receiving NSAIDs preoperatively (given the evening prior to the event along with Cerenia®).
  • Utilize gabapentin and amitriptyline as analgesics in the perioperative and postoperative setting.
  • Realize that you will face a challenge with respect to how you handle left over preservative free product as all product is preservative free at this time.
  • Not only will drug cost more but reverse distribution of unused schedule II product will have to be disposed of properly according to state law.

     
    Extended Information
     
   

There are several factors that appear to be responsible for this predicament.

  • In Oct of 2016, the DEA reduced the 2017 Aggregate Production Quota (APQ) for almost every Schedule II opiate by 25 percent compared to years prior. Apparently, they eliminated the 25% buffer built into the APQ; a buffer intended to guard against shortages. In the Fall of 2017 the DEA reduced the APQ by an additional 20%.
  • One distributor told us that hydromorphone underwent a recall last year creating strain on that product’s availability.
  • The impact of the 2017 hurricane season created strains on opioid supplies both by unexpectedly increasing demand and through decreased production at facilities damaged during the hurricanes.

For the time being, hydromorphone, low concentration morphine, and meperidine are the only pure mu agonists that we are likely to have access to and even then, availability will be intermittent. Availability varies from day to day, distributor to distributor, and region to region. Preservative free (PF) fentanyl is not currently available.

The author’s practice typically utilizes Patterson Veterinary, Amatheon Pharmaceuticals, and Southern Anesthesia & Surgical (SAS) as our primary sources for opioids. We utilize the DEA’s CSOS system to submit orders for schedule II drugs electronically. While this is a somewhat laborious application process once completed, ordering becomes much more efficient and efficiency is a key factor that increases the likelihood you will receive an ordered product when there is a rolling availability of drug from supplier.

Currently all morphine, all meperidine, and most hydromorphone products are only available as preservative free (PF) preparations; product labeled for single patient use. This presents quite a challenge in the veterinary practice setting where cost effectiveness is a must and especially when drug supplies are limited.  Wastage not only increases overall drug costs, increases in wasted agent also increase the costs associated with reverse distribution of unused drug.

Whether one uses a preservative free product over multiple days is a personal decision. It is not hard to find pharmacist-oriented veterinary professionals cautioning against ANY use of PF product past the day of first use:

You can also find anesthesiologists that argue for use of PF product over multiple days when handled with extreme aseptic care: The author’s practice currently utilizes ReturnLogistics as their reverse distributor:

The challenge over what to do with left over PF product is reduced when you purchase lower concentration product in smaller volume vials such as the 2 mg/ml hydromorphone in 1 ml vials (typically available in 25 count box); you minimize left over drug but the cost per mg of drug is substantially higher than other options. 

The challenge is greatest if you purchase higher concentration product in larger vials such as the 10 mg/ml hydromorphone in 50 ml vials (sold individually); you minimize cost per mg of drug, but you maximize the time over which the product will be used, and you maximize the need for reverse distribution.

As with many things, the final decision is up to the individual practitioner. Keep in mind that fentanyl product has been PF for a very long time as has been all standard commercial 0.3 mg/ml buprenorphine product.

Best estimates for when the preservative containing multidose vials of hydromorphone will return to the market is May of 2018. While you will hear rumors that we will eventually see the return of preservative containing multidose vials of morphine there isn’t a tentative release date at this time. Given that hydromorphone with preservative was originally scheduled to return in January of this year and has already been pushed back to May, the return of morphine with preservative is not likely any time in the foreseeable future.

As of June of 2018, 2 mg/ml hydromorphone with preservative in 10 ml vials has been available but in limited supply. The only other mu agonist with preservative that you may find available at this time is 10 mg/ml methadone in 20 ml vials. At last check it was unavailable and prohibitively expensive. It does not appear that we will ever see the return of multidose vials of morphine with preservative.

This spreadsheet will be updated from time to time; it provides a snapshot of drug availability and cost:

Buprenorphine is a useful partial mu agonist analgesic. Far more capable than butorphanol or nalbuphine (both kappa agonists), buprenorphine is well suited to procedures related to mild to moderate pain. Standard buprenorphine has always been preservative free and quite dilute at 0.3 mg/ml. At 1.8 mg/ml, Simbadol® is a much more concentrated form of buprenorphine. Simbadol® is quite simply a more concentrated form of buprenorphine, it is not a repositol formulation (as is SR buprenorphine). Simbadol® is a preserved product labeled for 56-day retention after first broaching the vial (when properly handled). Although labeled for high dose use delivered by the subcutaneous route, the use of Simdabol at conventional doses delivered by the IM and IV route represents quite a cost savings compared to commercial 0.3 mg/ml product.

Hydromorphone is a very versatile pure mu agonist being well suited to preanesthetic, maintenance anesthesia, intermittent bolus analgesia, analgesic CRI, and epidural use. These applications and dosing are covered elsewhere on the website. Our practice search page has recently been updated; conduct a hydromorphone search to help locate website resources:

Morphine is also a very versatile pure mu agonist being well suited to preanesthetic, maintenance anesthesia, intermittent slow bolus analgesia, analgesic CRI, and epidural use. These applications and dosing are covered on the website.

Meperidine is best suited to IM preanesthetic and intermittent IM analgesic use. While you may find references suggesting very slow IV administration is acceptable this author embraces what appears to be the majority opinion which is that IV use is specifically discouraged due to the adverse potential associated with significant histamine release. Meperidine appears to have a significantly shorter duration of effect compared to hydromorphone and morphine; as short as an hour in cats and a few hours in dogs. We do not recommend meperidine use for maintenance anesthesia, IV rapid bolus analgesia, analgesic CRI, or epidural use.

While methadone is well suited to preanesthetic use when vomiting is unwanted, at last check it was unavailable and prohibitively expensive. 

Procedural sedation

Kappa agonists provide little analgesia and have a short duration of effect; they are best suited to use in procedural sedation combinations for patients undergoing procedures associated with minimal discomfort such as imaging and the collection of blood and urine samples.  Kappa agonists are not recommended for patients undergoing any meaningful surgery.

For procedural sedation, the author uses 0.2 mg/kg butorphanol or 0.4 mg/kg nalbuphine along with midazolam and at least one sedative/tranquilizer (acepromazine, dexmedetomidine) assuming the patient is healthy.

Preanesthetics

Our practice currently uses hydromorphone for preanesthetics. If we found ourselves out of hydromorphone, fentanyl, and morphine we would look to meperidine and dose it in the 5 to 10 mg/kg range for dogs and 5 mg/kg for cats.

While buprenorphine is an option best suited for preanesthetic use in patients undergoing procedures associated with mid to low level pain such as spays and neuters and minor soft tissue surgery, in the absence of any pure mu agonist opioid options buprenorphine is a far better choice than kappa agonists like  butorphanol and nalbuphine for any painful procedure. If buprenorphine was the only mu agonist available at a practice that was preparing a patient for a more painful procedure the author would recommend higher dose buprenorphine; our practice routinely uses 0.030 to 0.040 mg/kg (as high as 0.060 mg/kg) IM and IV dosing for dogs and cats.

Simbadol® is currently labeled for subcutaneous use in feline patients only administered at 0.24 mg/kg. When used as the sole opioid for feline patients, Simbadol® should be administered to the feline patient ~1 hour prior to the procedure.

The Webmaster wishes to note that his practice is currently using Simbadol® for all of the practice's buprenorphine needs:

  • 0.020 to 0.060 mg/kg given by the IM or IV route.
  • 0.24 mg/kg given to cats only by the subcutaneous route for 24-hour duration effect repeated in 24 hours if desired for up to three total injections each spaced about 24 hours apart.

Simbadol® is far more cost-effective than the 0.3 mg/ml commercial human buprenorphine product. Simbadol® is labeled for 56-day retention after first vial entry.

Although many believe that a kappa agonist needs to be included with buprenorphine in preanesthetic protocols to achieve adequate patient sedation, combinations with buprenorphine, midazolam, and a sedative/tranquilizer alone generally provide more than adequate calming effect.

Alpha-2 agonists provide a significant analgesic and sedative synergism when combined with opioids. The author utilizes alpha-2 agonists on all healthy patients regardless of age with very few exceptions. The question about just how much analgesia you gain at the low doses we commonly use is a worthy one but it’s a moot point given the variety of potential benefits when dexmedetomidine is included in a well thought out strategy.

The author includes midazolam in all patient preanesthetic combination strategies with very few exceptions; it is never used alone. Midazolam is extremely safe, enhances patient relaxation, reduces the need for other agents, and may provide a few hours of amnesia.

Analgesic CRIs

Fentanyl, hydromorphone, morphine are the drugs of choice when available. While this website lists a buprenorphine, butorphanol, and methadone CRI calculator the author has chosen NOT to use such CRIs and is unaware of any direct support for such CRIs. Meperidine should not be used in any analgesic CRI.

In the absence of fentanyl, hydromorphone, or morphine this author would utilize buprenorphine as an intermittent administration (0.020 to 0.060 mg/kg IM, IV q 6 to 8 hours) and then run an analgesic CRI utilizing lidocaine and ketamine along with midazolam and dexmedetomidine (depending on patient status).

Local/Regional Techniques

The author’s practice utilizes local/regional techniques for almost all surgical patients typically including more than one application for a given patient.

Simple techniques include incisional blocks, dental blocks, intercostal blocks, retrobulbar blocks, regional infiltration, intratesticular blocks, and intraperitoneal injections. Except for intraperitoneal injections, the author includes an opioid in the block to extend the expected analgesic benefit. Buprenorphine, hydromorphone, and morphine would all be well suited to this task.

Unfortunately, in the Fall of 2018, bupivacaine has been in very short supply. Ropivacaine is an excellent alternative but expect the cost to be about 10 times what our past bupivacaine product cost. Like the opioids above, bupivacaine and ropivacaine product will likely be preservative free increasing total cost of use due to drug wastage.

Remember, when performing nerve blocks, do not inject against resistance and be aware that blocks fail!

Epidurals: PF Hydromorphone is the current drug of choice (unless PF morphine is randomly available). The author would reach for buprenorphine if PF hydromorphone and PF morphine were unavailable. The author recommends that local agent be included in an epidural unless contraindicated by patient details. Nocita® is a liposomal bupivacaine product labeled for tissue infiltration during surgery for post-operative analgesia following cranial cruciate ligament surgery. It is labeled for single patient use. Analgesia may extend up to 72 hours.
Cost is a challenge given that the price per vial is in the $180 range when purchased individually and in the $160 range when purchased in the 4-pack.
Guided nerve blocks using ultrasound imaging and nerve stimulators are a very attractive way to improve patient analgesia but require additional equipment and expertise.
Local anesthetic toxicity is not necessarily a well-defined issue; not an exact science. The
The webmaster often follows this dosing structure:
  • Lidocaine, Mepivacaine - used alone
    • Dogs - 1 to 5 mg/kg/hour
    • Cats - 1 to 3 mg/kg/hour
  • Bupivacaine, Ropivacaine - used alone
    • Dogs - 1 to 5 mg/kg q 4 to 6 hours
    • Cats - 1 mg/kg q 4 to 6 hours
  • Combination dosing for dogs and cats:
    • 2 mg/kg total lidocaine + bupivacaine used locally
    • 1 to 3 mg/kg/hr lidocaine CRI
    • 1 mg/kg bupivacaine epidurally
The Egger-Love review linked to above has a nice review of the toxicity issue: Severe accidental local anesthetic toxicity is best managed with 20% lipid emulsion:

NSAIDs

Preperative use of NSAIDs has been associated with the potential for adverse effects especially if the practice does not provide effective blood pressure monitoring and effective blood pressure support. Even at our practice, we choose not to give standard COX-2 preferential NSAIDs preoperatively.

That being said, the COX-2 NSAIDs are an attractive option for most feline and canine patients if they are judged to be NSAID tolerant. Given COX-2 NSAIDs in the immediate postoperative phase helps reduce concerns regarding this group of drugs.

The release of the new piprant class NSAID, Galliprant®(grapiprant) has changed that discussion as Galliprant® has not yet shown a significant potential for renal, hepatic, or gastrointestinal harm. The author’s practice has a longstanding policy of having our clients administer a dose of Cerenia® before bedtime the night before an anesthetic event. Adding a dose of Galliprant® at the same time should be a serious consideration given that Galliprant® has a 24-hour duration of effect (and given that fact that an injectable version is not yet available).

Additional Analgesic Options

It is not uncommon for human patient to receive centrally acting oral analgesics a few hours preoperatively. As noted by Dr. Clifford Wolf and others, these agents could include calcium channel blockers (gabapentin, pregabalin) and reuptake inhibitors (duloxetine). The author’s practice routinely administers gabapentin orally the morning of a procedure.

References:

     
     
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Last modified: December 8, 2018 .